1,6-naphthyridine derivatives and their use to treat diabetes and related disorders

ABSTRACT

The invention relates generally to naphthyridine derivatives of the formula 
                 
 
wherein one of U, X, Y and Z is nitrogen and the others are C—R, where R is hydrogen or a substituent. More specifically, the invention relates to 1,6-naphthyridine derivatives and pharmaceutical compositions containing such derivatives. Methods of the invention comprise administration of a naphthyridine derivative of the invention for the treatment of diabetes and related disorders.

This is a continuing application of U.S. Ser. No. 10/253,215, filed Sep. 23, 2003, now U.S. Pat. No. 6,677,352, which claims priority from Provisional Application 60/324511 filed Sep. 26, 2001.

FIELD OF THE INVENTION

The present invention relates to 1,6-naphthyridine derivatives, pharmaceutical compositions containing them, and their use for treating diabetes and related disorders in a subject.

DESCRIPTION OF THE RELATED ART

Diabetes is characterized by impaired glucose metabolism manifesting itself among other things by an elevated blood glucose level in the diabetic patient. Underlying defects lead to a classification of diabetes into two major groups: type 1 diabetes, or insulin dependent diabetes mellitus (IDDM), arises when patients lack insulin-producing beta-cells in their pancreatic glands. Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), occurs in patients with impaired beta-cell function and alterations in insulin action.

The current treatment for type 1 diabetic patients is the injection of insulin, while the majority of type 2 diabetic patients are treated with agents that stimulate beta-cell function or with agents that enhance the tissue sensitivity of the patients towards insulin. The drugs presently used to treat type 2 diabetes include alpha-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, and metformin.

Over time almost one-half of type 2 diabetic subjects lose their response to these agents. Insulin treatment is instituted after diet, exercise, and oral medications have failed to adequately control blood glucose. The drawbacks of insulin treatment are the need for drug injection, the potential for hypoglycemia, and weight gain.

Because of the problems with current treatments, new therapies to treat type 2 diabetes are needed. In particular, new treatments to retain normal (glucose-dependent) insulin secretion are needed. Such new drugs should have the following characteristics: dependency on glucose for promoting insulin secretion, i e., compounds that stimulate insulin secretion only in the presence of elevated blood glucose; low primary and secondary failure rates; and preservation of islet cell function. The strategy to develop the new therapy disclosed herein is based on the cyclic adenosine monophosphate (cAMP) signaling mechanism and its effects on insulin secretion.

Metabolism of glucose promotes the closure of ATP-dependent K+ channels, which leads to cell depolarization and subsequent opening of Ca++ channels. This in turn results in the exocytosis of insulin granules. cAMP is a major regulator of glucose-stimulated insulin secretion. However, it has little if any effects on insulin secretion in the absence of or at low glucose concentrations (Weinhaus, A., et al., Diabetes 47: 1426-1435 (1998)). The effects of cAMP on insulin secretion are thought to be mediated by a protein kinase A pathway.

Endogenous secretagogues like pituitary adenylate cyclase activating peptide (PACAP), VIP, and GLP-1 use the cAMP system to regulate insulin secretion in a glucose-ependent fashion (Komatsu, M., et al., Diabetes 46: 1928-1938, (1997)). Also, phosphodiesterases (PDEs) are known to be involved in the regulation of the cAMP system.

PACAP is a potent stimulator of glucose-dependent insulin secretion from pancreatic beta cells. Three different PACAP receptor types (R1, R2, and R3) have been described (Harmar, A., et al., Pharmacol. Reviews 50: 265-270 (1998)). The insulinotropic action of PACAP is mediated by the GTP binding protein Gs. Accumulation of intracellular cAMP in turn activates nonselective cation channels in beta cells increasing [Ca++]i, and promoting the exocytosis of insulin-containing secretory granules.

Vasoactive intestinal peptide (VIP) is a 28 amino acid peptide that was first isolated from hog upper small intestine (Said and Mutt, Science 169: 1217-1218, 1970; U.S. Pat. No. 3,879,371). This peptide belongs to a family of structurally related, small polypeptides that includes helodermin, secretin, the somatostatins, and glucagon. The biological effects of VIP are mediated by the activation of membrane-bound receptor proteins that are coupled to the intracellular cAMP signaling system. These receptors were originally known as VIP-R1 and VIP-R2, however, they were later found to be the same receptors as PACAP-R2 and PACAP-R3.

GLP-1 is released from the intestinal L-cell after a meal and functions as an incretin hormone (i.e., it potentiates glucose-induced insulin release from the pancreatic beta cell). It is a 37-amino acid peptide that is differentially expressed by the glucagon gene, depending upon tissue type. The clinical data that support the beneficial effect of raising cAMP levels in β-cells have been collected with GLP-1. Infusions of GLP-1 in poorly controlled type 2 diabetics normalized their fasting blood glucose levels (Gutniak, M., et al., New Eng. J. Med. 326:1316-1322, (1992)) and with longer infusions improved the beta cell function to those of normal subjects (Rachman, J. et al., Diabetes 45: 1524-1530, (1996)). A recent report has shown that GLP-1 improves the ability of β-cells to respond to glucose in subjects with impaired glucose tolerance (Byrne M., et al., Diabetes 47: 1259-1265 (1998)). All of these effects, however, are short-lived because of the short half-life of the peptide.

SUMMARY OF THE INVENTION

The invention provides compounds, pharmaceutical compositions, and methods of using the same for treating diabetes and related disorders. Compounds of the invention include compounds of formula (II)

wherein

-   R^(1′) is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8     carbon atoms, alkynyl of 2-8 carbon atoms, and A-R⁹, or -   R^(1′) is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9     carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂ and O,     cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms,     5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2     heteroatoms selected from N, S(═O)₀₋₂ and O, and 5-7 membered     heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected     from N, S(═O)₀₋₂ and O, wherein said heterocycloalkyl and said     heterocycloakenyl may further be fused with phenyl or a 5-6 membered     heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N,     S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in     said heterocycloalkyl or heterocycloalkenyl may be oxidized to     C(═O), all of which may be substituted with 1-3 of R¹⁰; -   R¹⁰ is selected from nitro, nitrile, hydroxy, halogen, acyl of 1-6     carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon     atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms,     alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms,     cycloalkoxy of 3-6 carbon atoms, aryl of 6-10 carbon atoms,     heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N,     S(═O)₀₋₂ and O, NR¹¹R¹², C(═O)OR¹¹, C(═O)NHR¹¹, NHC(═O)R¹³,     NHS(═O)₂R¹³, S(═O)₀₋₂R¹³, S(═O)₂NHR¹¹, cycloalkyl of 3-6 carbon     atoms, cycloalkenyl of 3-6 carbon atoms, 5-7 membered     heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected     from N, S(═O)₀₋₂ and O, and 5-7 membered heterocycloalkenyl of 3-6     carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O,     wherein said heterocycloalkyl and said heterocycloakenyl may further     be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon     atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂ and O, and/or     wherein one or more of the carbon atoms in said heterocycloalkyl or     heterocycloalkenyl may be oxidized to C(═O); -   R¹³ is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6     carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon     atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6     carbon atoms; -   R¹¹ and R¹² are independently selected from hydrogen, alkyl of 1-6     carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon     atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon     atoms, and cycloalkenyl of 4-6 carbon atoms; -   A is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon     atoms, alkynyl of 2-8 carbon atoms, and haloalkyl of 1-8 carbon     atoms; -   R⁹ is selected from hydroxy, alkoxy of 1-6 carbon atoms, cycloalkoxy     of 3-6 carbon atoms, O-A-R¹⁴, NR¹¹R¹²; or -   R⁹ is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9     carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂ and O,     cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms,     all of which may be substituted with 1-3 of R¹⁰, or -   R⁹ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, and 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, S(═O)₀₋₂ and O, wherein said heterocycloalkyl and     said heterocycloakenyl may further be fused with phenyl or a 5-6     membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected     from N, S(═)₀₋₂ and O, and/or wherein one or more of the carbon     atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized     to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl     may be substituted with 1-3 of R¹⁰; -   R¹⁴ is selected from cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of     5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms     and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, and 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, S(═O)₀₋₂ and O, all of which may be substituted     with 1-3 of R¹⁰; -   with the proviso for R^(1′) that when A is CH₂, R⁹ is not optionally     substituted biphenyl; -   R^(2′) is selected from NR¹⁵R¹⁶, S(O)₀₋₂R¹⁷, and OR¹⁷; -   R¹⁵ is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of     2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cylcoalkyl of 3-8     carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered     heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected     from N, S(═O)₀₋₂ and O, 5-7 membered heterocycloalkenyl of 3-6     carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O,     A-R⁹, C(═O)R¹⁸, C(═O)NHR¹⁸, S(═O)₂NHR¹⁸; -   R¹⁸ is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9     carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂ and O,     cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms,     5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2     heteroatoms selected from N, S(═O)₀₋₂ and O, and 5-7 membered     heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected     from N, S(═O)₀₋₂ and O, all of which may be substituted with 1-3 of     R¹⁰, or -   R¹⁸ is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6     carbon atoms, and alkynyl of 2-6 carbon atoms, all of which may be     substituted with 1-3 of halogen or alkoxy of 1-6 carbon atoms, or -   R¹⁸ is A-R⁹; -   R¹⁶ is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8     carbon atoms, alkynyl of 2-8 carbon atoms, and A-R⁹, or -   R¹⁶ is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9     carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂ and O,     cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms,     5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2     heteroatoms selected from N, S(═O)₀₋₂ and O, and 5-7 membered     heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected     from N, S(═O)₀₋₂ and O, all of which may be substituted with 1-3 of     R¹⁰, or -   R¹⁵ and R¹⁶ combine, together with the nitrogen atom to which they     are attached, to form a heteroaryl of 2-9 carbon atoms and 1-4     heteroatoms selected from N, S(═O)₀₋₂ and O, or a 5-7 membered     heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected     from N, S(═O)₀₋₂ and O, 5-7 membered heterocycloalkenyl of 3-6     carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O,     wherein said heterocycloalkyl and said heterocycloakenyl may further     be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon     atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂ and O, and/or     wherein one or more of the carbon atoms in said heterocycloalkyl or     heterocycloalkenyl may be oxidized to C(═O), all of which may be     substituted with 1-3 of R¹⁰; -   R¹⁷ is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8     carbon atoms, and alkynyl of 2-8 carbon atoms, haloalkyl of 1-8     carbon atoms, A-R⁹, or -   R¹⁷ is selected from aryl of 6-10 carbon atoms, hetcroaryl of 2-9     carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂ and O,     cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms,     5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2     heteroatoms selected from N, S(═O)₀₋₂ and O, and 5-7 membered     heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected     from N, S(═O)₀₋₂ and O, all of which may be substituted with 1-3 of     R¹⁰; -   R^(3′) is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9     carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂ and O,     cylcoalkyl of 3-8 carbon atoms, heterocycloalkyl of 3-6 carbon atoms     and 1-2 heteroatoms selected from N, S(O)₀₋₂, and O, cycloalkenyl of     4-8 carbon atoms, and heterocycloalkenyl of 3-6 carbon atoms and 1-2     heteroatoms selected from N, S(O)₀₋₂ and O, all of which may be     substituted with 1-3 of R¹⁰, or -   R^(3′) is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6     carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon     atoms, hydrogen, nitro, halogen, NR¹⁹R²⁰, A-OR¹⁹, A-NR¹⁹R²⁰, and     A-R²⁰; -   R¹⁹ and R²⁰ are independently selected from hydrogen, alkyl of 1-6     carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon     atoms, haloalkyl of 1-6 carbon atoms, and A-R⁹, or -   R¹⁹ and R²⁰ are independently selected from aryl of 6-10 carbon     atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected     from N, S(O)₀₋₂ and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl     of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, S(O)₀₋₂ and O, 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, S(O)₀₋₂ and O, wherein said heterocycloalkyl and     said heterocycloakenyl may further be fused with phenyl or a 5-6     membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected     from N, S(═O)₀₋₂ and O, and/or wherein one or more of the carbon     atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized     to C(═O), all of which may be substituted with 1-3 of R¹⁰; -   R^(4′) is selected from ═O, ═S, and OR²¹; -   R²¹ is hydrogen, or -   R²¹ is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8     carbon atoms, alkynyl of 2-20 8 carbon atoms, cycloalkyl of 3-8     carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered     heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected     from N, S(═O)₀₋₂ and O, and 5-7 membered heterocycloalkenyl of 3-6     carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O,     all of which may be substituted with 1-3 of R¹⁰; -   R^(5′), R^(7′), and R^(8′) are independently selected from     cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms,     aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and     1-4 heteroatoms, all of which may be substituted with 1-3 of R¹⁰, or     R^(5′), R^(7′), and R^(8′) are independently selected from 5-7     membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, S(═O)₀₋₂ and O, and 5-7 membered heterocycloalkenyl     of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂     and O, wherein said heterocycloalkyl and said heterocycloakenyl may     further be fused with phenyl or a 5-6 membered heteroaryl of 2-5     carbon atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂ and O,     and/or wherein one or more of the carbon atoms in said     heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O),     wherein said heterocycloalkyl or said heterocycloalkenyl may be     substituted with 1-3 of R¹⁰, A-R²³, A-NR²⁴R²⁵, C(═O)R²⁴, C(═O)OR²⁴,     C(═O)NR²⁴R²⁵, S(═O)₂R²⁶, A-C(═O)R²⁴, A-C(═O)OR²⁴, or A-C(═O)NR²⁴R²⁵,     or -   R^(5′), R^(7′), and R^(8′) are independently selected from hydrogen,     halogen, nitrile, nitro, hydroxy, alkyl of 1-8 carbon atoms, alkenyl     of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, haloalkyl of 1-8     carbon atoms, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon     atoms, cycloalkoxy of 3-8 carbon atoms, A-R²³, A(OR²²)—R²³, NR²⁷R²⁸,     A-NR²⁷R²⁸, A-Q-R²⁹, Q-R²⁹, Q-A-NR²⁴R²⁵, C(═O)R²⁴, C(═O)OR²⁴,     C(═O)NR²⁴R²⁵, A-C(═O)R²⁴, A-C(═O)OR²⁴, and A-C(═O)NR²⁴R²⁵; -   Q is selected from O and S(═O)₀₋₂; -   R²² is selected from hydrogen, alkyl of 1-8 carbon atoms, haloalkyl     of 1-8 carbon atoms, and cycloalkyl of 3-8 carbon atoms; -   R²³ is selected from hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy     of 1-8 carbon atoms, and cycloalkoxy of 3-8 carbon atoms, or -   R²³ is selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of     4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9     carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂, and O,     all of which may be substituted with 1-3 of R¹⁰, or -   R²³ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, and 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, O, S(═O)₀₋₂, wherein said heterocycloalkyl and said     heterocycloakenyl may further be fused with phenyl or a 5-6 membered     heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N,     S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in     said heterocycloalkyl or heterocycloalkenyl may be oxidized to     C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may     be substituted with 1-3 of R¹⁰; -   with the proviso for A(OR²²)—R²³ that when R²³ is selected from     hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms,     and cycloalkoxy of 3-8 carbon atoms, A is not CH; -   R²⁴ and R²⁵ are independently selected from hydrogen, alkyl of 1-6     carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon     atoms, haloalkyl of 1-6 carbon atoms, and A-R²³, or -   R²⁴ and R²⁵ are independently selected from cycloalkyl of 3-6 carbon     atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms,     and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from     N, S(═O)₀₋₂, and O, all of which may be substituted with 1-3 of R¹⁰,     or -   R²⁴ and R²⁵ are independently selected from 5-7 membered     heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected     from N, O, S(═O)₀₋₂, and 5-7 membered heterocycloalkenyl of 3-6     carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂,     wherein said heterocycloalkyl and said heterocycloakenyl may further     be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon     atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂ and O, and/or     wherein one or more of the carbon atoms in said heterocycloalkyl or     heterocycloalkenyl may be oxidized to C(═O), wherein said     heterocycloalkyl or said heterocycloalkenyl may be substituted with     1-3 of R¹⁰, or -   R²⁴ and R²⁵ combine, together with the nitrogen atom to which they     are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂, and O, a 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, S(═O)₀₋₂, and O, or a heteroaryl of 2-9 carbon     atoms and 1-4 heteroatoms, wherein said heterocycloalkyl and said     heterocycloakenyl may further be fused with phenyl or a 5-6 membered     heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N,     S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in     said heterocycloalkyl or heterocycloalkenyl may be oxidized to     C(═O), all of which may be substituted with 1-3 of R¹⁰; -   R²⁶ is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6     carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon     atoms, A(OR²²)—R²³, and A-R²³, or -   R²⁶ is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of     3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9     carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂, and O,     all of which may be substituted with 1-3 of R¹⁰, or -   R²⁶ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, and 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, O, S(═O)₀₋₂, wherein said heterocycloalkyl and said     heterocycloakenyl may further be fused with phenyl or a 5-6 membered     heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N,     S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in     said heterocycloalkyl or heterocycloalkenyl may be oxidized to     C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may     be substituted with 1-3 of R¹⁰; -   R²⁷ is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of     2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6     carbon atoms, and A-R²³, or -   R²⁷ is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of     3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9     carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂, and O,     all of which may be substituted with 1-3 of R¹⁰, or -   R²⁷ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, and 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, O, S(═O)₀₋₂, wherein said heterocycloalkyl and said     heterocycloakenyl may further be fused with phenyl or a 5-6 membered     heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N,     S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in     said heterocycloalkyl or heterocycloalkenyl may be oxidized to     C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may     be substituted with 1-3 of R¹⁰; -   R²⁸ is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of     2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6     carbon atoms, A-R²³, C(═O)R²⁴, C(═O)OR²⁶, C(═O)NR₂₅R³⁰S(═O)₂R²⁶,     A-C(═O)R²⁴, A-C(═O)OR²⁴, and A-C(═O)NR²⁴R²⁵, or -   R²⁸ is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of     3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9     carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂, and O,     all of which may be substituted with 1-3 of R¹⁰, or -   R²⁸ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, and 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, O, S(═O)₀₋₂, wherein said heterocycloalkyl and said     heterocycloakenyl may further be fused with phenyl or a 5-6 membered     heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N,     S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in     said heterocycloalkyl or heterocycloalkenyl may be oxidized to     C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may     be substituted with 1-3 of R¹⁰; -   R³⁰ is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6     carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon     atoms, A(OR²²)—R²³, and A-R²³, or -   R³⁰ is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of     3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9     carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂, and O,     all of which may be substituted with 1-3 of R¹⁰, or -   R³⁰ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, and 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, O, S(═O)₀₋₂, wherein said heterocycloalkyl and said     heterocycloakenyl may further be fused with phenyl or a 5-6 membered     heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N,     S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in     said heterocycloalkyl or heterocycloalkenyl may be oxidized to     C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may     be substituted with 1-3 of R¹⁰, or -   R²⁵ and R³⁰ combine, together with the nitrogen atom to which they     are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂, and O, a 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, S(═O)₀₋₂, and O, or a heteroaryl of 2-9 carbon     atoms and 1-4 heteroatoms, all of which may be substituted with 1-3     of R¹⁰; -   R²⁹ is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6     carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon     atoms, A-R²³, A-C(═O)R²⁴, A-C(═O)OR²⁴, A-C(═O)NR²⁴R²⁵, A-NR²⁷R²⁸, or -   R²⁹ is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of     3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9     carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂, and O,     all of which may be substituted with 1-3 of R¹⁰, or -   R²⁹ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, and 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, O, S(═O)₀₋₂, wherein said heterocycloalkyl and said     heterocycloakenyl may further be fused with phenyl or a 5-6 membered     heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N,     S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in     said heterocycloalkyl or heterocycloalkenyl may be oxidized to     C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may     be substituted with 1-3 of R¹⁰;     and pharmaceutically acceptable salts thereof.

Another aspect of the invention includes compounds of formula (II), wherein R^(1′) is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R⁹, or

-   R^(1′) is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9     carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂ and O,     cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms,     5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2     heteroatoms selected from N, S(═O)₀₋₂ and O, and 5-7 membered     heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected     from N, S(═O)₀₋₂ and O, wherein said heterocycloalkyl and said     heterocycloakenyl may further be fused with phenyl or a 5-6 membered     heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N,     S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in     said heterocycloalkyl or heterocycloalkenyl may be oxidized to     C(═O), all of which may be substituted with 1-3 of R¹⁰; -   R¹⁰ is selected from nitro, nitrile, hydroxy, halogen, acyl of 1-6     carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon     atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms,     alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms,     cycloalkoxy of 3-6 carbon atoms, aryl of 6-10 carbon atoms,     heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N,     S(═O)₀₋₂ and O, NR¹¹R¹², C(═O)OR¹¹, C(═O)NHR¹¹, NHC(═O)R¹³,     NHS(═O)₂R¹³, S(═O)₀₋₂R¹³, S(═O)₂NHR¹¹, cycloalkyl of3-6 carbon     atoms, cycloalkenyl of 3-6 carbon atoms, 5-7 membered     heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected     from N, S(═O)₀₋₂ and O, and 5-7 membered heterocycloalkenyl of 3-6     carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O,     wherein said heterocycloalkyl and said heterocycloakenyl may further     be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon     atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂ and O, and/or     wherein one or more of the carbon atoms in said heterocycloalkyl or     heterocycloalkenyl may be oxidized to C(═O); -   R¹³ is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6     carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon     atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6     carbon atoms; -   R¹¹ and R¹² are independently selected from hydrogen, alkyl of 1-6     carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon     atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon     atoms, and cycloalkenyl of 4-6 carbon atoms; -   A is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon     atoms, alkynyl of 2-8 carbon atoms, and haloalkyl of 1-8 carbon     atoms; -   R⁹ is selected from hydroxy, alkoxy of 1-6 carbon atoms, cycloalkoxy     of 3-6 carbon atoms, O-A-R¹⁴, NR¹¹R¹²; or -   R⁹ is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9     carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂ and O,     cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms,     all of which may be substituted with 1-3 of R¹⁰, or -   R⁹ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, and 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, S(═O)₀₋₂ and O, wherein said heterocycloalkyl and     said heterocycloakenyl may further be fused with phenyl or a 5-6     membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected     from N, S(═O)₀₋₂ and O, and/or wherein one or more of the carbon     atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized     to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl     may be substituted with 1-3 of R¹⁰; -   R¹⁴ is selected from cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of     5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms     and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, and 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, S(═O)₀₋₂ and O, all of which may be substituted     with 1-3 of R¹⁰; -   with the proviso for R^(1′) that when A is CH₂, R⁹ is not optionally     substituted biphenyl; -   R^(2′) is NR¹⁵R¹⁶; -   R¹⁵ is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of     2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cylcoalkyl of 3-8     carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered     heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected     from N, S(═O)₀₋₂ and O, 5-7 membered heterocycloalkenyl of 3-6     carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O,     A-R⁹, C(═O)R¹⁸, C(═O)NHR¹⁸, S(═O)₂NHR¹⁸; -   R¹⁸ is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9     carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂ and O,     cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms,     5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2     heteroatoms selected from N, S(═O)₀₋₂ and O, and 5-7 membered     heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected     from N, S(═O)₀₋₂ and O, all of which may be substituted with 1-3 of     R¹⁰, or -   R¹⁸ is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6     carbon atoms, and alkynyl of 2-6 carbon atoms, all of which may be     substituted with 1-3 of halogen or alkoxy of 1-6 carbon atoms, or -   R¹⁸ is A-R⁹; -   R¹⁶ is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8     carbon atoms, alkynyl of 2-8 carbon atoms, and A-R⁹, or -   R¹⁶ is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9     carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂ and O,     cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms,     5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2     heteroatoms selected from N, S(═O)₀₋₂ and O, and 5-7 membered     heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected     from N, S(═O)₀₋₂ and O, all of which may be substituted with 1-3 of     R¹⁰, or -   R¹⁵ and R¹⁶ combine, together with the nitrogen atom to which they     are attached, to form a heteroaryl of 2-9 carbon atoms and 1-4     heteroatoms selected from N, S(═O)₀₋₂ and O, or a 5-7 membered     heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected     from N, S(═O)₀₋₂ and O, 5-7 membered heterocycloalkenyl of 3-6     carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O,     wherein said heterocycloalkyl and said heterocycloakenyl may further     be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon     atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂ and O, and/or     wherein one or more of the carbon atoms in said heterocycloalkyl or     heterocycloalkenyl may be oxidized to C(═O), all of which may be     substituted with 1-3 of R¹⁰; -   R^(3′) is selected from cycloalkyl of 3-6 carbon atoms,     heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected     from N, S(O)₀₋₂ and O, both of which may be substituted with 1-3 of     R¹⁰, or -   R^(3′) is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6     carbon atoms, hydrogen, nitro, halogen, NR¹⁹R²⁰, A-OR¹⁹, A-NR¹⁹R²⁰     and A-²⁰; -   R¹⁹ and R²⁰ are independently selected from hydrogen, alkyl of 1-6     carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon     atoms, haloalkyl of 1-6 carbon atoms, and A-R⁹, or -   R¹⁹ and R²⁰ are independently selected from aryl of 6-10 carbon     atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected     from N, S(O)₀₋₂ and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl     of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, S(O)₀₋₂ and O, 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, S(O)₀₋₂ and O, wherein said heterocycloalkyl and     said heterocycloakenyl may further be fused with phenyl or a 5-6     membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected     from N, S(═O)₀₋₂ and O, and/or wherein one or more of the carbon     atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized     to C(═O), all of which may be substituted with 1-3 of R¹⁰; -   R^(4′) is selected from ═O, ═S, and OR²¹; -   R²¹ is hydrogen, or -   R²¹ is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8     carbon atoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-8 carbon     atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered     heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected     from N, S(═O)₀₋₂ and O, and 5-7 membered heterocycloalkenyl of 3-6     carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O,     all of which may be substituted with 1-3 of R¹⁰; -   R^(5′) is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl     of 4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon     atoms and 1-3 heteroatoms, all of which may be substituted with 1-3     of R¹⁰, or -   R^(5′) is selected from 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O and 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, S(═O)₀₋₂ and O, wherein one or more of the carbon     atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized     to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl     may be substituted with 1-3 of R¹⁰, A-R²³, A-NR²⁴R²⁵, C(═O)R²⁴,     C(═O)OR²⁴, C(═O)NR²⁴R²⁵, S(═O)₂R²⁶, A-C(═O)R²⁴, A-C(═O)OR²⁴, or     A-C(═O)NR²⁴R²⁵, or -   R^(5′) is selected from hydrogen, halogen, nitrile, nitro, hydroxy,     alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of     2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6     carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6     carbon atoms, A-R²³, A(OR²²)—R²³, NR²⁷R²⁸, A-NR²⁷R²⁸, A-Q-R²⁹,     Q-R²⁹, Q-A-NR²⁴R²⁵, C(═O)R²⁴, C(═O)OR²⁴, C(═O)NR²⁴R²⁵, A-C(═O)R²⁴,     A-C(═O)OR²⁴, and A-C(═O)NR²⁴R²⁵; -   Q is selected from O and S(═O)₀₋₂; -   R²² is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl     of 1-6 carbon atoms, and cycloalkyl of 3-6 carbon atoms; -   R²³ is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy     of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, or -   R²³ is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of     4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon     atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂, and O, all of     which may be substituted with 1-3 of R¹⁰, or -   R²³ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, and 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, O, S(═O)₀₋₂, wherein one or more of the carbon     atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized     to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl     may be substituted with 1-3 of R¹⁰; -   with the proviso for A(OR²²)—R²³ that when R²³ is selected from     hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms,     and cycloalkoxy of 3-6 carbon atoms, A is not CH; -   R²⁴ and R²⁵ are independently selected from hydrogen, alkyl of 1-6     carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon     atoms, haloalkyl of 1-6 carbon atoms, and A-R²³, or -   R²⁴ and R²⁵ are independently selected from cycloalkyl of 3-6 carbon     atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic     heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N,     S(═O)₀₋₂, and O, all of which may be substituted with 1-3 of R¹⁰, or -   R²⁴ and R²⁵ are independently selected from 5-7 membered     heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected     from N, O, S(═O)₀₋₂, and 5-7 membered heterocycloalkenyl of 3-6     carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂,     wherein one or more of the carbon atoms in said heterocycloalkyl or     heterocycloalkenyl may be oxidized to C(═O), wherein said     heterocycloalkyl or said heterocycloalkenyl may be substituted with     1-3 of R¹⁰, or -   R²⁴ and R25 combine, together with the nitrogen atom to which they     are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂, and O, a 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, S(═O)₀₋₂, and O, or a monocyclic heteroaryl of 2-5     carbon atoms and 1-3 heteroatoms, wherein one or more of the carbon     atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized     to C(═O), all of which may be substituted with 1-3 of R¹⁰; -   R26 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6     carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon     atoms, A(OR²²)—R²³, and A-R²³, or -   R²⁶ is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of     3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon     atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂, and O, all of     which may be substituted with 1-3 of R¹⁰, or -   R²⁶ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, and 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, O, S(═O)₀₋₂, wherein one or more of the carbon     atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized     to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl     may be substituted with 1-3 of R¹⁰; -   R²⁷ is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of     2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6     carbon atoms, and A-R²³, or -   R²⁷ is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of     3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon     atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂, and O, all of     which may be substituted with 1-3 of R¹⁰, or -   R²⁷ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, and 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, O, S(═O)₀₋₂, wherein one or more of the carbon     atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized     to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl     may be substituted with 1-3 of R¹⁰; -   R²⁸ is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of     2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6     carbon atoms, A-R²³, C(═O)R²⁴, C(═O)OR, C(═O)NR²⁵R³⁰, S(═O)₂R²⁶,     A-C(═O)R²⁴, A-C(═O)OR²⁴, and A-C(═O)NR²⁴R²⁵, or -   R²⁸ is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of     3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms     and 1-3 heteroatoms selected from N, S(═O)₀₋₂, and O, all of which     may be substituted with 1-3 of R¹⁰, or -   R²⁸ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, and 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, O, S(═O)₀₋₂, wherein one or more of the carbon     atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized     to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl     may be substituted with 1-3 of R¹⁰; -   R³⁰ is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6     carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon     atoms, A(OR²²)—R²³, and A-R²³, or -   R³⁰ is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of     3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon     atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂, and O, all of     which may be substituted with 1-3 of R¹⁰, or -   R³⁰ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, and 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, O, S(═O)₀₋₂, wherein one or more of the carbon     atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized     to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl     may be substituted with 1-3 of R¹⁰, or -   R²⁵ and R³⁰ combine, together with the nitrogen atom to which they     are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂, and O, a 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, S(═O)₀₋₂, and O, or a monocyclic heteroaryl of 2-5     carbon atoms and 1-3 heteroatoms, all of which may be substituted     with 1-3 of R¹⁰; and -   R²⁹ is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6     carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon     atoms, A-R²³, A-C(═O)R²⁴, A-C(═O)OR²⁴, A-C(═O)NR²⁴R²⁵, A-NR²⁷R²⁸, or -   R29 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of     3-6 carbon atoms, phenyl, monocyclic heteroaryl of 2-5 carbon atoms     and 1-3 heteroatoms selected from N, S(═O)₀₋₂, and O, all of which     may be substituted with 1-3 of R¹⁰, or -   R²⁹ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon     atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, and 5-7     membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms     selected from N, O, S(═O)₀₋₂, wherein one or more of the carbon     atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized     to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl     may be substituted with 1-3 of R¹⁰. -   R^(7′) and R^(8′) are independently selected from cycloalkyl of 3-6     carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms     and 1-3 heteroatoms, all of which may be substituted with 1-3 of     R¹⁰, or -   R^(7′) and R^(8′) are independently selected from 5-7 membered     heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected     from N, S(═O)₀₋₂, and/or wherein one of the carbon atoms in said     heterocycloalkyl may be oxidized to C(═O), wherein said     heterocycloalkyl may be substituted with 1-3 of R¹⁰, A-R²³,     A-NR²⁴R²⁵, C(═O)R²⁴, C(═O)OR²⁴, C(═O)NR²⁴R²⁵, S(═O)₂R²⁶, A-C(═O)R²⁴,     A-C(═O)OR²⁴, or A-C(═O)NR²⁴R25, or -   R^(7′) and R^(8′) are independently selected from hydrogen, halogen,     nitrile, nitro, hydroxy, alkyl of 1-6 carbon atoms, haloalkyl of 1-6     carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon     atoms, cycloalkoxy of 3-6 carbon atoms, A-R²³, A(OR²²)—R²³, NR²⁷R²⁸,     A-NR²⁷R²⁸, A-Q-R²⁹, Q-R²⁹, Q-A-NR²⁴R²⁵, C(═O)R²⁴, C(═O)OR²⁴,     C(═O)NR²⁴R²⁵, A-C(═O)R²⁴, A-C(═O)OR²⁴, and A-C(═O)NR²⁴R²⁵;     and pharmaceutically acceptable salts thereof.

Methods of the invention provide for the treatment or prevention of diabetes, including Type 1 and Type 2 diabetes, and related disorders by administration of a compound of the invention. Related disorders include maturity-onset diabetes of the young (MODY), latent autoimmune diabetes adult (LADA), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), gestational diabetes, and metabolic syndrome X.

In other embodiments, methods of the invention provide for the administration of a compound of the invention in combination with a PPAR agonist, an insulin sensitizer, a sulfonylurea, an insulin secretagogue, a hepatic glucose output lowering compound, an α-glucosidase inhibitor or insulin. PPAR agonist includes rosiglitazone and pioglitazone. Sulfonylureas include glibenclamide, glimepiride, chlorpropamide, and glipizide. Insulin secretagogues include GLP-1, GIP, PAC/VPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, and glipizide. α-glucosidase inhibitors include acarbose, miglitol and voglibose. A hepatic glucose output lowering compound is metformin.

In another embodiment, methods of the invention provide for the administration of a compound of the invention in combination with an HMG-CoA reductase inhibitor, nicotinic acid, a bile acid sequestrant, a fibric acid derivative, antihypertensive drug, or an anti-obesity drug. Anti-obesity drugs include a β-3 agonist, a CB-1 antagonist, and a lipase inhibitor.

In another embodiment of the invention, methods are provided for the treatment or prevention of secondary causes of diabetes, such as glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug-induced diabetes.

Finally, methods of the invention provide for increasing the sensitivity of pancreatic beta cells to an insulin secretagogue, by administering a compound of the invention. Insulin secretagogues include GLP-1, GIP, PAC/VPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, and glipizide.

The present invention therefore provides compounds and methods for the treatment of diabetes and related disorders. These and other aspects of the invention will be more apparent from the following description and claims.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates generally to naphthyridine derivatives of the formula

wherein one of U, X, Y and Z is nitrogen and the others are C—R, where R is hydrogen or a substituent such as R^(5′), R^(7′) or R^(8′), as described above for formula (II). R^(1′), R^(2′), R^(3′) and R^(4′) are as defined above for formula (II). The invention relates to compounds of formula (II), as described above, and to compounds of formula (I)

wherein R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ correspond to R^(1′), R^(2′), R3′, R^(4′), R^(5′), R^(7′) and R^(8′), respectively, of formula (II). Such compounds may be used in the treatment of diabetes and related disorders.

In one embodiment, the invention relates to compounds of formula (II), as described above. In another embodiment, the invention relates to compounds of formula (II), wherein R^(1′) is phenyl, which may be substituted with 1-3 of R¹⁰, R^(2′) is NR¹⁵R¹⁶, R^(3′) is selected from cycloalkyl of 3-6 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)₀₋₂ and O, both of which may be substituted with 1-3 of R¹⁰, or R^(3′) is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR¹⁹R²⁰, A-OR¹⁹, A-NR^(19 R) ²⁰ and A-R20, and R^(4′) is ═O.

In another embodiment, the invention relates to methods of treating diabetes and related disorders by administration of compounds of formula (II). Preferred methods relate to the treatment of Type 2 diabetes. In methods of the invention, compounds of formula (II) may be administered in combination with PPAR agonist, insulin sensitizers, sulfonylureas, insulin secretagogues, metformin, α-glucosidase inhibitors and insulin. In another embodiment, compounds of formula (II) are administered in combination with an HMG-CoA reductase inhibitor, nicotinic acid, a bile acid sequestrant, a fibric acid derivative, an anti-hypertensive drug or an anti-obesity drug.

In other methods of the invention, compounds of formula (II) are administered to treat or prevent secondary causes of diabetes or to increase the sensitivity of pancreatic beta cells to an insulin secretagogue.

General Preparative Methods

The compounds of the invention may be prepared by use of known chemical reactions and procedures. Nevertheless, the following general synthetic schemes are presented to aid the reader in synthesizing compounds of this invention, with more detailed particular examples being presented below in the experimental section describing the working examples.

In general, compounds of Formula (I) (R⁴ is ═O) may be prepared from the appropriately substituted nicotinic acid through several routes summarized in Flow Diagram I to IV. Compounds of Formula (II) (R^(4′) is ═O) may be prepared from the appropriately substituted nicotinic acid through the route summarized in Flow diagram V. The close analogy between Flow Diagram I and V demonstrates that the routes used to synthesize Formula (I) may be applied to synthesize Formula (II). The routes shown in Flow Diagram II to IV maybe used to synthesize Formula (II) from appropriately substituted nicotinic acid.

The nicotinic acids used in the above flow diagrams could be purchased from commercial sources, prepared according to Flow Diagram VI, or prepared according to literature in this field (Biorg. Med. Chem. Lett. 2001, 475-477; J. Prakt. Chem. 2002, 33; Eur. J. Org. Chem. 2001, 1371; J. Org. Chem. 2000, 65, 4618; J. Med. Chem. 1997, 40, 2674; Bioorg. Med. Chem. Lett. 2000, 10, 1151; U.S. Pat. No. 3,838,156, etc.).

Further manipulations of Formula (I) (when R⁴ is ═O) and (II) (when R^(4′) is ═O) could lead to more diversely substituted compounds. These manipulations include aromatic nucleophilic substitutions, metal-mediated couplings, reductions, oxidations, amide formations, etc.

Flow Diagram VII illustrates alkylation, and amide, urea, and sulfonamide formations in Formula (I) when R²=NHR¹⁶. Similar transformations could be carried out in Formula (II) when R^(2′)=NHR¹⁶.

Flow Diagram VIII and IX illustrate transformations at R³ in Formula (I). These transformations could also be applied to R^(3′) in Formula (II).

Flow Diagram X illustrates manipulations of R⁴ in formula (I), which could also be used on R^(4′) in formula (II).

Flow Diagram XI illustrates manipulations of R⁶ in formula (I). These manipulations could also be applied to R⁵ and R⁷ in formula (I), R5′, R^(7′), and R^(8′) in formula (II).

Flow Diagram XIl illustrates manipulations on R⁷ of formula (I). These manipulations could also be applied to R⁵ in formula (I), R^(5′) and R^(7′) in formula (II).

Flow Diagram XIII illustrates manipulations on R⁵ of formula (I). These manipulations could also be applied to R⁷ in formula (I), R^(5′) and R^(7′) in formula (II).

Flow Diagram XIV illustrates the transformations of some functional groups which are present in Formula (I) or (II).

Alternative Forms Of Novel Compounds

Also included in the compounds of the present invention are (a) the stereoisomers thereof, (b) the pharmaceutically-acceptable salts thereof, (c) the tautomers thereof, (d) the protected acids and the conjugate acids thereof, and (e) the prodrugs thereof.

(a) The Stereoisomers

The stereoisomers of these compounds may include, but are not limited to, enantiomers, diastereomers, racemic mixtures and combinations thereof. Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention. Isomers may include geometric isomers. Examples of geometric isomers include, but are not limited to, cis isomers or trans isomers across a double bond. Other isomers are contemplated among the compounds of the present invention. The isomers may be used either in pure form or in admixture with other isomers of the inhibitors described above.

(b) The Pharmaceutically-Acceptable Salts

Pharmaceutically-acceptable salts of the compounds of the present invention include salts commonly used to form alkali metal salts or form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids. Examples of organic and sulfonic classes of organic acids includes, but are not limited to, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, furmaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, N-hydroxybutyric, salicyclic, galactaric and galacturonic acid and combinations thereof

(c) The Tautomers

Tautomers of the compounds of the invention are encompassed by the present invention. Thus, for example, a carbonyl includes its hydroxy tautomer.

(d) The Protected Acids and the Conjugate Acids

The protected acids include, but are not limited to, esters, hydroxyamino derivatives, amides and sulfonamides.

(e) The Prodrugs

The present invention includes the prodrugs and salts of the prodrugs. Formation of prodrugs is well known in the art in order to enhance the properties of the parent compound; such properties include solubility, absorption, biostability and release time (see “Pharmaceutical Dosage Form and Drug Delivery Systems” (Sixth Edition), edited by Ansel et al., publ. by Williams & Wilkins, pgs. 27-29, (1995) which is hereby incorporated by reference). Commonly used prodrugs are designed to take advantage of the major drug biotransformation reactions and are also to be considered within the scope of the invention. Major drug biotransformation reactions include N-dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation and acetylation (see Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 11-13, (1996), which is hereby incorporated by reference).

Dosages And Treatment Regimen

Dosage levels of the compounds of this invention typically are from about 0.001 mg to about 10,000 mg daily, preferably from about 0.005 mg to about 1,000 mg daily. On the basis of mg/kg daily dose, either given in a single dose or in divided doses, dosages typically range from about 0.001/75 mg/kg to about 10,000/75 mg/kg, preferably from about 0.005/75 mg/kg to about 1,000/75 mg/kg.

The total daily dose of each drug can be administered to the patient in a single dose, or in multiple subdoses. Typically, subdoses can be administered two to six times per day, preferably two to four times per day, and even more preferably two to three times per day. Doses can be in immediate release form or sustained release form sufficiently effective to obtain the desired control over the diabetic condition.

The dosage regimen to prevent, treat, give relief from, or ameliorate a diabetic condition or disorder, or to otherwise protect against or treat a diabetic condition with the combinations and compositions of the present invention is selected in accordance with a variety of factors. These factors include, but are not limited to, the type, age, weight, sex, diet, and medical condition of the subject, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicology profiles of the particular inhibitors employed, whether a drug delivery system is utilized, and whether the inhibitors are administered with other active ingredients. Thus, the dosage regimen actually employed may vary widely and therefore deviate from the preferred dosage regimen set forth above.

Pharmaceutical Compositions

For the prophylaxis or treatment of the conditions and disorders referred to above, the compounds of this invention can be administered as the compound per se. Alternatively, pharmaceutically-acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to that of the parent compound.

The compounds of the present invention also can be administered with an acceptable carrier in the form of a pharmaceutical composition. The carrier must be acceptable in the sense of being compatible with the other ingredients of the composition and must not be intolerably deleterious to the recipient. The carrier can be a solid or a liquid, or both, and preferably is formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from about 0.05% to about 95% by weight of the active compound(s) based on a total weight of the dosage form. Other pharmacologically active substances can also be present, including other compounds usefull in the treatment of a diabetic condition.

The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a therapeutically effective dose for the treatment intended. The active compounds and compositions, for example, may be administered orally, sublingually, nasally, pulmonarily, mucosally, parenterally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically. Unit dose formulations, particularly orally administrable unit dose formulations such as tablets or capsules, generally contain, for example, from about 0.001 to about 500 mg, preferably from about 0.005 mg to about 100 mg, and more preferably from about 0.01 to about 50 mg, of the active ingredient. In the case of pharmaceutically acceptable salts, the weights indicated above for the active ingredient refer to the weight of the pharmaceutically active ion derived from the salt.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, a capsule, a suspension, an emulsion, a paste, a solution, a syrup or other liquid form. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. If administered by mouth, the compounds may be admixed with, for example, lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.

Oral delivery of the compounds of the present invention can include formulations, as are well known in the art, to provide immediate delivery or prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms. Immediate delivery formulations include, but are not limited to, oral solutions, oral suspensions, fast-dissolving tablets or capsules, sublingual tablets, disintegrating tablets and the like. Prolonged or sustained delivery formulations include, but are not limited to, pH sensitive release of the active ingredient from the dosage form based on the changing pH of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form. The intended effect is to extend the time period over which the active drug molecule is delivered to the site of action by manipulation of the dosage form. Thus, enteric-coated and enteric-coated controlled release formulations are within the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl-cellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester.

Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the inhibitor(s) and the carrier (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the inhibitor(s) with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet can be prepared by compressing or molding a powder or granules of the inhibitors, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant inert diluent and/or surface active/dispersing agent(s). Molded tablets can be made, for example, by molding the powdered compound in a suitable machine.

Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water . Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound of the present invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the inhibitors in an inert base such as gelatin and glycerin or sucrose and acacia.

Formulations for parenteral administration, for example, may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one is or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

Pharmaceutically acceptable carriers encompass all the foregoing and the like. The pharmaceutical compositions of the invention can be prepared by any of the well-known techniques of pharmacy, such as admixing the components. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks.

Methods Of Use

The present invention also includes methods for the treatment of diabetes and related diseases and conditions. One such method comprises the step of administering to a subject in need thereof, a therapeutically effective amount of one or more compounds of formula (II).

Compounds of formula (II) may be used in methods of the invention to treat diseases, such as diabetes, including both Type 1 and Type 2 diabetes. Such methods may also delay the onset of diabetes and diabetic complications. Other diseases and conditions that may be treated or prevented using compounds of formula (II) in methods of the invention include: Maturity-Onset Diabetes of the Young (MODY) (Herman, et al., Diabetes 43:40 (1994)), Latent Autoimmune Diabetes Adult (LADA) (Zimmet, et al., Diabetes Med. 11:299 (1994)), impaired glucose tolerance (IGT) (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Supp. 1) S5 (1999)), impaired fasting glucose (IFG) (Charles, et al., Diabetes 40:796 (1991)), gestational diabetes (Metzger, Diabetes, 40:197 (1991), and metabolic syndrome X.

Compounds of formula (II) may also be used in methods of the invention to treat secondary causes of diabetes (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Supp. 1), S5 (1999)). Such secondary causes include glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug-induced diabetes. Drugs that may induce diabetes include, but are not limited to, pyriminil, nicotinic acid, glucocorticoids, phenytoin, thyroid hormone, β-adrenergic agents, α-interferon and drugs used to treat HIV infection.

The methods and compounds of the present invention may be used alone or in combination with additional therapies and/or compounds known to those skilled in the art in the treatment of diabetes and related disorders. Alternatively, the methods and compounds described herein may be used, partially or completely, in combination therapy.

Compounds of formula (II) may also be administered in combination with other known therapies for the treatment of diabetes, including PPAR agonists, sulfonylurea drugs, non-sulfonylurea secretagogues, α-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, hepatic glucose output lowering compounds, insulin and anti-obesity drugs. Such therapies may be administered prior to, concurrently with or following administration of the compound of formula (II). Insulin includes both long and short acting forms and formulations of insulin. PPAR agonist may include agonists of any of the PPAR subunits or combinations thereof For example, PPAR agonist may include agonists of PPAR-α, PPAR-65 , PPAR-δ or any combination of two or three of the subunits of PPAR. PPAR agonists include, for example, rosiglitazone and pioglitazone. Sulfonylurea drugs include, for example, glyburide, glimepiride, chlorpropamide, and glipizide. α-glucosidase inhibitors that may be useful in treating diabetes when administered with a compound of formula (II) include acarbose, miglitol and voglibose. Insulin sensitizers that may be useful in treating diabetes when administered with a compound of formula (II) include thiazolidinediones and non-thiazolidinediones. Hepatic glucose output lowering compounds that may be usefull in treating diabetes when administered with a compound of formula (II) include metformin, such as Glucophage and Glucophage XR. Insulin secretagogues that may be useful in treating diabetes when administered with a compound of formula (II) include sulfonylurea and non-sulfonylurea drugs: GLP-1, GIP, PAC/VPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, glipizide. GLP-1 includes derivatives of GLP-1 with longer half-lives than native GLP-1, such as, for example, fatty-acid derivatized GLP-1 and exendin. In one embodiment of the invention, compounds of formula (II) are used in combination with insulin secretagogues to increase the sensitivity of pancreatic beta cells to the insulin secretagogue.

Compounds of formula (II) may also be used in methods of the invention in combination with anti-besity drugs. Anti-obesity drugs include β-3 agonists, CB-1 antagonists, appetite suppressants, such as, for example, sibutramine (Meridia), and lipase inhibitors, such as, for example, orlistat (Xenical).

Compounds of formula (II) may also be used in methods of the invention in combination with drugs commonly used to treat lipid disorders in diabetic patients. Such drugs include, but are not limited to, HMG-CoA reductase inhibitors, nicotinic acid, bile acid sequestrants, and fibric acid derivatives. Compounds of formula (II) may also be used in combination with anti-hypertensive drugs, such as, for example, β-blockers and ACE inhibitors.

Such co-therapies may be administered in any combination of two or more drugs (e.g., a compound of formula (I) in combination with an insulin sensitizer and an anti-obesity drug). Such co-therapies may be administered in the form of pharmaceutical compositions, as described above.

Terms

As used herein, various terms are defined below.

When introducing elements of the present invention or the preferred embodiment(s) thereof, the articles “a”, “an”, “the” and “said” are intended to mean that there are one or more of the elements. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.

The term “subject” as used herein includes mammals (e.g., humans and animals).

The term “treatment” includes any process, action, application, therapy, or the like, wherein a subject, including a human being, is provided medical aid with the object of improving the subject's condition, directly or indirectly, or slowing the progression of a condition or disorder in the subject.

The phrase “therapeutically-effective” means the amount of each agent administered that will achieve the goal of improvement in a diabetic condition or disorder severity, while avoiding or minimizing adverse side effects associated with the given therapeutic treatment.

The term “pharmaceutically acceptable” means that the subject item is appropriate for use in a pharmaceutical product.

The term “prodrug” includes a compound that is a drug precursor that, following administration to a subject and subsequent absorption, is converted to an active species in vivo. Conversion to the active, species in vivo is typically via some process, such as metabolic conversion. An example of a prodrug is an acylated form of the active compound.

The following definitions pertain to the structure of the compounds: In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified, for example, alkyl of 1-8 carbon atoms or C1-C8 alkyl. The use of a term designating a monovalent radical where a divalent radical is appropriate shall be construed to designate the divalent radical and vice versa. Unless otherwise specified, conventional definition of terms controls and conventional stable atom valences are presumed and achieved in all formulas and groups.

When symbols such as “A-Q-R” is used, it refers to a group which is formed by linking group A, group Q and group R in the designated order and the attachment of this group “A-Q-R” is any position on group A to form a stable structure. Group Q may be linked to any position on group A to form a stable structure and group R may be linked to any position on group Q to form a stable structure.

When symbols such as “A(OR′)—R” is used, it refers to a group which is formed by substituting group A with both group OR′ and group R and the attachment of this group “A(OR′)—R” is any position on group A to form a stable structure. Group OR′ and group R maybe linked to any position on group A to form a stable structure.

The term “halogen” refers to a halogen radical selected from fluoro, chloro, bromo or iodo.

The term “alkyl” refers to a saturated aliphatic hydrocarbon radical. “Alkyl” refers to both branched and unbranched alkyl groups. Examples of “alkyl” include alkyl groups that are straight chain alkyl groups containing from one to ten carbon atoms and branched alkyl groups containing from three to ten carbon atoms. Other examples include alkyl groups that are straight chain alkyl groups containing from one to six carbon atoms and branched alkyl groups containing from three to six carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), 1,1-dimethylethyl (tert-butyl), and the like. It may be abbreviated “Alk”. It should be understood that any combination term using an “alk” or “alkyl” prefix refers to analogs according to the above definition of “alkyl”. For example, terms such as “alkoxy”, “alkylthio”, “alkylamino” refer to alkyl groups linked to a second group via an oxygen, sulfur, or nitrogen atom, respectively.

The term “haloalkyl” refers to an alkyl group in which one or more hydrogen atoms are replaced with halogen atoms. This term in exemplified by groups such as trifluomethyl. The more preferred haloalkyl groups are alkyl groups substituted with one or more fluro or chloro. The term “haloalkoxy” refers to haloalkyl groups linked to a second group via an oxygen atom.

The term “alkenyl” refers to a mono or polyunsatuarted aliphatic hydrocarbon radical. The mono or polyunsaturated aliphatic hydrocarbon radical contains at least one carbon-carbon double bond. “Alkenyl” refers to both branched and unbranched alkenyl groups, each optionally partially or fully halogenated. Examples of “alkenyl” include alkenyl groups that are straight chain alkenyl groups containing from two to ten carbon atoms and branched alkenyl groups containing from three to ten carbon atoms. Other examples include alkenyl groups which are straight chain alkenyl groups containing from two to six carbon atoms and branched alkenyl groups containing from three to six carbon atoms. This term is exemplified by groups such as ethenyl, propenyl, n-buteny), isobutenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, decenyl, and the like.

The term “alkynyl” refers to a mono or polyunsatuarted aliphatic hydrocarbon radical. The mono or polyunsaturated aliphatic hydrocarbon radical contains at least one carbon-carbon triple bond. “Alkynyl” refers to both branched and unbranched alkynyl groups, each optionally partially or fully halogenated. Examples of “alkynyl” include alkynyl groups that are straight chain alkynyl groups containing from two to ten carbon atoms and branched alkynyl groups containing from four to ten carbon atoms. Other examples include alkynyl groups that are straight chain alkynyl groups containing from two to six carbon atoms and branched alkynyl groups containing from four to six carbon atoms. This term is exemplified by groups such as ethynyl, propynyl, octynyl, and the like.

The term “cycloalkyl” refers to the mono- or polycyclic analogs of an alkyl group, as defined above. Unless otherwise specified, the cycloalkyl ring may be attached at any carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. Examples of cycloalkyl groups are saturated cycloalkyl groups containing from three to ten carbon atoms. Other examples include cycloalkyl groups containing three to six carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclononyl, cyclodecyl, norbornane, adamantyl, and the like.

The term “cycloalkenyl” refers to the mono- or polycyclic analogs of an alkenyl group, as defined above. Unless otherwise specified, the cycloalkenyl ring may be attached at any carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. Examples of cycloalkenyl groups are cycloalkenyl groups containing from four to ten carbon atoms. Other examples include cycloalkenyl groups containing four to six carbon atoms. Exemplary cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornene, and the like.

The term “heterocycloalkyl” refers to the mono- or polycyclic structures of “cycloalkyl” where one or more of the carbon atoms are replaced by one or more atoms independently chosen from nitrogen, oxygen, or sulfur atoms. Any nitrogen atom maybe optionally oxidized or quanternized, and any sulfur atom maybe optionally oxidized. Unless otherwise specified, the heterocycloalkyl ring may be attached at any carbon atom or heteroatom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom or heteroatom which results in a stable structure. Examples of heterocycloalkyl groups are saturated heterocycloalkyl groups containing from two to nine carbon atoms and one to four heteroatoms chosen independently from nitrogen, oxygen, or sulfur atoms. Examples of heterocycloalkyl groups include morpholino, pyrazino, tetrahydrofurano, and the like.

The term “heterocycloalkenyl” refers to the mono- or polycyclic structures of “cycloalkenyl” where one or more of the carbon atoms are replaced by one or more atoms independently chosen from nitrogen, oxygen, or sulfur atoms. Any nitrogen atom maybe optionally oxidized or quanternized, and any sulfur atom maybe optionally oxidized. Unless otherwise specified, the heterocycloalkenyl ring may be attached at any carbon atom or heteroatom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom or heteroatom which results in a stable structure. Examples of heterocycloalkenyl groups are saturated heterocycloalkenyl groups containing from two to nine carbon atoms and one to four heteroatoms chosen independently from nitrogen, oxygen, or sulfur atoms. Examples of heterocycloalkenyl groups include dihydropyran, dihydrofuran, and the like.

The term “cycloalkyloxy” refers to a monovalent radical of the formula —O-cycloalkyl, i.e., a cycloalkyl group linked to a second group via an oxygen atom.

The term “acyl” refers to a monovalent radical of the formula —(═O)-alkyl and —C(═O)-cycloalkyl, i.e., an alkyl or cycloakyl group linked to a second group via caronyl group C(═O), wherein said alkyl maybe further substituted with cycloalkyl, aryl, or heteroaryl. Examples of acyl groups include —C(═O)Me (acetyl), —C(═O)CH₂-cyclopropyl (cyclopropylacetyl), —C(═O)CH₂Ph (phenylacetyl), and the like.

The term “aryl” refers to 6-10 membered mono or polycyclic aromatic carbocycles, for example, phenyl and naphthyl. Unless otherwise specified, the aryl ring may be attached at any carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable carbon atom which results in a stable structure. The term “aryl” refers to non-substituted aryls and aryls optionally substituted with one or more of the following groups: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C4-C6 cycloalkenyl, C2-C6 alkynyl, nitro, cyano, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, amino, C1-C6 alkylamino (for example, —NHMe and —N(Me)₂), C1-C6 acyl, thiol, alkylthio, carboxylic acid. All the above subtsitutions can further be substituted with optionally selected groups to form a stable structure. It may be abbreviated “Ar”. It should be understood that any combination term using an “ar” or “aryl” prefix refers to analogs according to the above definition of “aryl”. For example, terms such as “aryloxy”, “arylthio”, “arylamino” refer to aryl groups linked to a second group via an oxygen, sulfur, or nitrogen atom, respectively.

The term “heteroaryl” refers to a stable 5-8 membered (but preferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclic aromatic heterocycle radical. Each heteroaryl contains 1-10 carbon atoms and from 1 to 5 heteroatoms independently chosen from nitrogen, oxygen and sulfur, wherein any sulfur heteroatom may optionally be oxidized and any nitrogen heteroatom may optionally be oxidized or quaternized. Unless otherwise specified, the heteroaryl ring may be attached at any suitable heteroatom or carbon atom that results in a stable structure and, if substituted, may be substituted at any suitable heteroatom or carbon atom which results in a stable structure. The term “heteroaryl” includes heteroaryl groups that are non-substituted or those optionally substituted with one or more of the following groups: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C4-C6 cycloalkenyl, C2-C6 alkynyl, nitro, cyano, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, amino, C1-C6 alkylamino (for example, —NHMe and —N(Me)₂), C1-C6 acyl, thiol, alkylthio, carboxylic acid. Examples of “heteroaryl” include radicals such as furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl. Terms such as “heteroaryloxy”, “heteroarylthio”, “heteroarylamino” refer to heteroaryl groups linked to a second group via an oxygen, sulfur, or nitrogen atom, respectively.

The terms “optional” or “optionally” mean that the subsequently described event or circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

A comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.

For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

Abbreviations and Acronyms

When the following abbreviations are used throughout the disclosure, they have the following meaning:

CH₂Cl₂ methylene chloride THF tetrahydrofuran CH₃CN acetonitrile Na₂SO₄ anhydrous sodium sulfate MgSO₄ anhydrous magnesium sulfate DMSO dimethylsulfoxide EtOAc ethyl acetate Et₂O diethyl ether Et₃N triethylamine H₂ hydrogen CO carbon monoxide HCl hydrochloric acid Hex hexanes ¹H NMR proton nuclear magnetic resonance HPLC high performance liquid chromatography K₂CO₃ potassium carbonate Cs₂CO₃ cesium carbonate NH₄Cl ammonium chloride LC/MS liquid chromatography/mass spectroscopy MeOH methanol MS ES mass spectroscopy with electrospray NaHCO₃ sodium bicarbonate NaOH sodium hydroxide RT retention time h hour min minutes Pd(OAc)₂ palladium acetate Ni(dppp)Cl₂ [1,3-bis(diphenylphosphino)propane]dichloronickel(II) DMF N,N-dimethylformamide EDCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride LTMP Lithium tetramethylpiperidine BuLi butyllithium TLC thin layer chromatography TFA trifluoacetic acid TMEDA tetramethylethylenediamine BINAP 2,2′-bis(diphenylphosphino)-1,1′binaphthyl HOBt 1-hydroxybenzotriazole hydrate NaH sodium hydride MeMgBr methylmagnesium bromide DPPP (diphenylphosphino)propane DME dimethoxyethane AlCl₃ aluminum chloride TEA triethyl amine CS₂ carbon disulfide MeI methyl iodide t-BuOK potassium tert-butoxide KHMDS potassium hexamethyldisilazide LiHMDS lithium hexamethyldisilazide NaOBr sodium hypobromite Br₂ bromine Conc. Concentrated Pd/C palladium on carbon EtOH ethanol NH₃ ammonia NaOMe sodium methoxide PPh₃ triphenylphosine NaH sodium hydride LDA lithium diisopropylamide SOCl₂ thionyl chloride MsCl methanesulfonyl chloride DMAP 4-dimethylaminopyridine NMM 4-methylmorpholine AcOH acetic acid Na₂S₂O₃ sodium thiosulfate H₂SO₄ sulfuric acid CHCl₃ chloroform MnO₂ manganese(IV) oxide LAH lithium aluminum hydride ADDP 1,1′-(azodicarbonyl)-dipiperidine EDTA ethylenediaminetetraacetic acid CCl₂FCClF₂ 1,1,2-trichlorotrifluoroethane NaNO₂ sodium nitrite

Preparative Examples

Examples of preparations of compounds of the invention are provided in the following detailed synthetic procedures. In tables 1A and 2A, the synthesis of each compound is referenced back to these exemplary preparative steps. In tables 1B and 2B, the proposed synthesis of each compound is referenced back to these exemplary preparative steps.

All reactions were carried out under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Commercial grade reagents and solvents were used without further purification.

Unless otherwise stated, the term ‘concentration under reduced pressure’ refers to use of a Buchi rotary evaporator at approximately 15 mm of Hg. All temperatures are reported uncorrected in degrees Celsius (° C.). Unless otherwise indicated, all parts and percentages are by volume.

Proton (¹H) nuclear magnetic resonance (NMR) spectra were measured with a Varian Mercury (300 MHz) or a Bruker Avarice (500 MHz) spectrometer with either Me₄Si (δ0.00) or residual protonated solvent (CHCl₃ δ7.26; MeOH δ3.30; DMSO δ2.49) as standard. The NMR data of the synthesized examples, which are not disclosed in the following detailed charaterizations, are in agreements with their corresponding structural assignements.

The HPLC-MS spectra were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2×23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluents were A: 2% CH₃CN in water with 0.02% TFA and B: 2% water in CH₃CN with 0.018% TFA. Gradient elution from 10% B to 95% over 3.5 minutes at a flow rate of 1.0 mulmin was used with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. Total run time was 6.5 minutes.

Elemental analyses were conducted by Robertson Microlit Labs, Madison N.J. The results of elemental analyses, if conducted but not disclosed in the following detailed charaterizations, are in agreements with their corresponding structural assignements.

The following specific examples are presented to illustrate the invention related to Formula (I) as described herein, but they should not be construed as limiting the scope of the invention in any way.

Intermediate A 2,6-dichloro-4-methyl-nicotinic acid

Method 1

A solution of sodium nitrite (2.73 g, 39.6 mmol) in water (15 mL) was added slowly to a solution of commercially available (Maybridge) 2,6-dichloro-4-methyl-nicotinamide (4.5 g, 22 mmol) in concentrated sulfuric acid resulting in evolution of heat and brown gas. The mixture was stirred at room temperature for 15 min, and then heated to 60° C. for 7 h. The solution was cooled to 0° C. and then water (15 mL) was added. The resulting white precipitate was collected by filtration and washed with hexane. The aqueous filtrate was extracted with EtOAc (3×) and the combined organic extracts were dried over MgSO₄ and concentrated in vacuo. The residue was combined with the white precipitate to afford 2,6-dichloro-4-methyl-nicotinic acid (4.39 g, 97%) as a white solid: LCMS RT: 1.20 min, MH⁺: 206.3.

Method 2

Concentrated nitric acid (1-4 mL) was added to cooled (0° C.) concentrated sulfuric acid (43 mL) maintaining the internal temperature below 10° C. After addition, the acid mixture was heated to 70° C. and commercially available (Avocado) 2,6-dichloro-4-methylnicotinonitrile (20.0 g, 107 mmol) was added. The temperature was raised until the internal temperature of the reaction reached 105° C. At this point the heating was stopped and after 2 h, TLC analysis revealed that the reaction was complete. The reaction mixture was cooled to room temperature, and slowly added to ice (100 g) with strong agitation. The solid was filtered and washed with cold water (10 mL). The solid was dissolved in EtOAc (100 mL) and the solution was dried over Na₂SO₄ and concentrated to give 2,6-dichloro-4-methyl-nicotinic acid (21.0 g, 96%) as a white solid: R_(f)=0.20 (1:1 EtOAc:Hex).

Intermediate B 2,6-dichloro-4-methyl-nicotinoyl chloride

A solution of 2,6-dichloro-4-methyl-nicotinic acid (3.94 g, 19.1 mmol) in thionyl chloride (18 mL) was heated to 80° C. for 2 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-4-methyl-nicotinoyl chloride as yellow oil. It was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.

Intermediate C 3,3-dichloro-1-(2,6-dichloro-4-methyl-pyridin-3-yl)-propenone

A solution of the 2,6-dichloro-4-methyl-nicotinoyl chloride from the previous reaction in CH₂Cl₂ (10 mL) was added slowly to a cooled (0° C.) and stirred slurry solution of AlCl₃ (2.54 g, 19.1 mmol) in CH₂Cl₂ (54 mL). After 15 min, vinylidene chloride (1.5 mL, 1.85 g, 19.1 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was poured over ice and the ice slurry was acidified using 1 N HCl (50 mL). Stirring was continued for 20 min and then the product was extracted with CH₂Cl₂ (3×). The combined organic extracts were dried over Na₂SO₄ and concentrated in vacuo to give 3,3-dichloro-1-(2,6-dichloro-4-methyl-pyridin-3-yl)-propenone (4.22 g, 77%) as a yellow oil: LCMS RT: 3.25, MH⁺: 284.3, R_(f)=0.47 (4:1 Hex:EtOAc).

Intermediate D 1-(2,6-Dichl ro-4-methyl-pyridin-3-yl)-3,3-bis-phenylamino-propenone

A solution of aniline (4.04 mL, 44.4 mmol) in TEA (6.2 mL, 44.4 mmol) was added slowly to a cooled (0° C.) and stirred solution of 3,3-dichloro-1-(2,6-dichloro-4-methyl-pyridin-3-yl)-propenone (4.22 g, 14.8 mmol) in dioxane (50 mL). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated in vacuo until most of the solvent was removed and then the residue was diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with water, dried over Na₂SO₄ and concentrated in vacuo. Silica gel flash chromatography of the residue using 7:1 EtOAc:Hex gave 1-(2,6-dichloro-4-methyl-pyridin-3-yl)-3,3-bis-phenylamino-propenone as yellow solid (2.22 g, 40%): LCMS RT: 3.21 min; MH⁺: 398.2, R_(f)=0.27 (2:1 Hex:EtOAc).

Intermediate E 7-Chloro-5-methyl-1-phenyl-2-phenylamino-1H-[1,8]-naphthyridin-4-one

A mixture of 1-(2,6-dichloro-4-methyl-pyridin-3-yl)-3,3-bis-phenylamino-propenone (2.17 g, 5.45 mmol) and t-BuOK (1.10 g, 9.81 mmol) in dioxane (55 mL) was heated to 80° C. overnight. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Silica gel flash chromatography of the residue using 1:1 EtOAc:Hex provided 7-chloro-5-methyl-1-phenyl-2-phenylamino-1H-[1,8]naphthyridin-4-one (1.297 g, 66%) as an orange solid: LCMS RT: 2.52 min, MH⁺: 362.3, R_(f)=0.18 (1:1 EtOAc:Hex) This transformation can also be accomplished by using the combination of other aprotic solvents such as DMF, and THF with other bases such as NaH.

Intermediate F 2,6-dichloro-4-(trifluoromethyl)nicotinic acid

Method 1

A solution of NaNO₂ (9.59 g, 139 mmol) in water (95 mL) was added slowly to a solution of commercially available (Oakwood) 2,6-dichloro-4-(trifluoromethyl)nicotinamide (20.0 g, 77 mmol) in conc. H₂SO₄ resulting in evolution of heat and brown gas. The mixture was stirred at room temperature for 15 min, and then heated to 60° C. for 18 h. The solution was cooled to 0° C. and then water (15 mL) was added. The resulting mixture was extracted with Et₂O (3×) and the combined organic extracts were dried over MgSO₄ and concentrated in vacuo. The residue was triturated with hexanes and vacuum-filtered to afford 2,6-dichloro-4-(trifluoromethyl)nicotinic acid (19 g, 95%) as an off-white solid: R_(f)=0.30 (9:1 CH₂Cl₂:MeOH), ¹H-NMR (d₆-DMSO, 300 MHz) δ8.18 (s, 1H).

Method 2

Conc. HNO₃ (13.3 mL) was added to cooled (0° C.) conc. H₂SO₄ (60 mL) maintaining the internal temperature below 10° C. After addition, the acid mixture was heated to 70° C. and commercially available (Maybridge) 2,6-dichloro-4-(trifluoromethyl)nicotinonitrile (20.0 g, 83 mmol) was added. The temperature was raised until the internal temperature of the reaction reached 100° C. After heating for 1 h TLC analysis revealed that the reaction was complete. The reaction mixture was cooled to room temperature, and slowly added to ice (100 g) with strong agitation and extracted with Et₂O (3×). The organic layers were combined and washed with brine. The solution was dried over Na₂SO₄ and concentrated in vacuo to give 2,6-dichloro-4-(trifluoromethyl)nicotinic acid (19.1 g, 89%) as an off-white solid: R_(f)=0.30 (9:1 CH₂Cl₂:MeOH), ¹H-NMR (d₆-DMSO, 300 MHz) δ8.18 (s, 1H).

Intermediate G 2,6dichloro-4-(trifluoromethyl)nicotinoyl chloride

A solution of 2,6-dichloro-4-(trifluoromethyl)nicotinic acid (3.22 g, 13.2 mmol) in thionyl chloride (9 mL) was heated at reflux for 3 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-4-(trifluoromethyl)nicotinoyl chloride as a yellow oil which was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.

Intermediate H 3,3-dichloro-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one

A solution of the 2,6-dichloro-4-(trifluoromethyl)nicotinoyl chloride from the previous reaction in CH₂Cl₂ (14 mL) was added slowly to a cooled (0° C.) and stirred slurry solution of AlCl₃ (4.4 g, 33.0 mmol) in CH₂Cl₂ (14 mL). After 15 min, vinylidene chloride (2.6 mL, 33.0 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was poured over ice and partitioned with CH₂Cl₂. The organic layer was collected and cooled to 0° C. before TEA (4.6 mL, 33 mmol) was added. After 15 min, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for an additional 30 min. The solution was washed with 1N HCl, NaHCO₃, and water. The organic layer was passed through a pad of silica gel and concentrated in vacuo to afford 3,3-dichloro-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one: (4.3 g, 95%) as a brown oil: LCMS RT: 3.59, MH⁺: 488.1, R_(f)=0.44 (EtOAc).

Intermediate I 3,3-dianilino-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one

A solution of aniline (18.4 mL, 202 mmol) in TEA (28.2 mL, 202 mmol) was added slowly to a cooled (0° C.) and stirred solution of 3,3-dichloro-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one (22.9 g, 67.4 mmol) in dioxane (220 mL). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was treated with 10% HCI and extracted with Et₂O (3×). The combined organic extracts were washed with brine, dried over Na₂SO₄ and concentrate in vacuo. Silica gel flash chromatography of the residue using 6:1 Hex:EtOAc gave 3,3-dianilino-1-[2,6 dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one as an off-white solid (13.10 g, 43%): ¹H-NMR (d₆-DMSO, 300 MHz) δ12.24 (br s, 1H), 9.20 (br s, 1H), 7.95 (s, 1H), 7.12-7.42 (m, 1H), 4.82 (s, 1H); R_(f)=0.60 (6:1 Hex:EtOAc).

Intermediate J 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one

A mixture of 3,3-dianilino-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one (12.9 g, 28.5 mmol) and t-BuOK (28.5 mL, 28.5 mmol, 1M in THF) in dioxane (200 mL) was heated at reflux overnight. The reaction was cooled, concentrated in vacuo, treated with saturated NH₄Cl and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over MgSO₄, and concentrated in vacuo. Silica gel flash chromatography of the residue using 6:1 Hex:EtOAc provided 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (11.2 g, 95%) as an off-white solid: LCMS RT: 3.00 min, MH⁺: 416.7, R_(f)=0.25 (3:1 Hex:EtOAc). This transformation can be accomplished by using the combination of other aprotic solvents such as DMF, and THF with other bases such as NaH.

Intermediate K

2,6-dichloro-5-fluoronicotinoyl chloride

A solution of commercially available (Aldrich) 2,6-dichloro-5-fluoronicotinic acid (5.00 g, 23.8 mmol) in thionyl chloride (15 mL) was heated at reflux for 3 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-5-fluoronicotinoyl chloride as a brown oil which was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.

Intermediate L 3,3-dichloro-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one

A solution of the 2,6-dichloro-5-fluoronicotinoyl chloride from the previous reaction in CH₂Cl₂ (25 mL) was added slowly to a cooled (0° C.) and stirred slurry solution of AlCl₃ (7.9 g, 59.5 mmol) in CH₂Cl₂ (25 mL). After 15 min, vinylidene chloride (4.75 mL, 59.5 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was poured over ice and partitioned with CH₂Cl₂. The organic layer was collected and cooled to 0° C. before TEA (8.3 mL, 59.5 mmol) was added. After 15 min, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for an additional 30 min. The solution was washed with 1N HCl, NaHCO₃, and water. The organic layer was passed through a pad of silica gel and concentrated in vacuo to afford 3,3-dichloro-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one: (6.1 g, 90%) as a brown oil: ¹H-NMR (d₆-DMSO, 300 MHz)δ8.43 (d, 1H, J=8.4 Hz), 7.56 (s, 1H), R_(f)=0.76 (3:1 Hex:EtOAc).

Intermediate M 3,3-dianilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one

To a 0° C. solution of 3,3-dichloro-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one (6.70 g, 23.2 mmol) in dioxane (50 mL) was added TEA (9.7 mL, 69.6) followed by aniline (6.3 mL, 69.6 mmol). After 1 h the reaction was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated in vacuo until most of the solvent was removed and then the residue was diluted with water and extracted with CH₂Cl₂ (2×). The combined organic extracts were washed with water, dried over Na₂SO₄ and concentrated in vacuo. Purification of the residue by silica gel Biotage chromatography provided 3,3-dianilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one as yellow solid (4.2 g, 49%): LCMS RT: 3.47 min; MH⁺: 402.6.

Intermediate N 2-anilino-7-chloro-4-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one

A mixture of 3,3-dianilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one (2.3 g, 5.7 mmol) and t-BuOK (1.28 g, 11.4 mmol) in dioxane (80 mL) was stirred at 80° C. overnight. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Silica gel flash chromatography of the residue provided 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (1.0 g, 50%) as a light yellow solid: LCMS RT: 2.60 min, MH⁺: 366.8. This transformation can be accomplished by using the combination of other aprotic solvents such as DMF, and THF with other bases such as NaH.

Intermediates N₁-N₁₂ were synthesized from 3,3-dichloro-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one as above for Intermediate N using the appropriate amine:

Intermediate N₁

LCMS RT: 2.81 min, MH⁺: 402.3

Intermediate N₂

LCMS RT: 2.73 min, MH⁺: 402.4

Intermediate N₃

LCMS RT: 2.30 min, MH⁺: 298.1

Intermediate N₄

LCMS RT: 2.88 min, MH⁺: 394.3

Intermediate N₅

LCMS RT: 2.78 min, MH⁺: 426.3

Intermediate N₆

LCMS RT: 3.09 min, MH⁺: 434.5

Intermediate N₇

LCMS RT: 3.07 min, MH⁺: 378.2

Intermediate N₈

LCMS RT: 3.15 min, MH⁺: 422.4

Intermediate N₉

LCMS RT: 2.90 min, MH⁺: 486.3

Intermediate N₁₀

LCMS RT: 2.22 min, MH⁺: 294.2

Intermediate N₁₁

LCMS RT: 3.05 min, MH⁺: 430.4

Intermediate N₁₂

LCMS RT: 2.51 min, MH⁺: 468.3

Intermediate N₁₃

LCMS RT: 3.10 min, MH⁺: 430.4

Intermediate O 2,6-dichloronicotinoyl chloride

A solution of commercially available (Aldrich) 2,6-dichloro-nicotinic acid (2.0 g, 10.4 mmol) in thionyl chloride (10 mL) was heated to 80° C. for 2 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-nicotinoyl chloride as yellow oil which was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.

Intermediate P 3,3-dichloro-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one

A solution of the 2,6-dichloro-nicotinoyl chloride (1.0 g, 4.76 mmol) from the previous reaction in CH₂Cl₂ (5 mL) was added slowly to a cooled (0° C.) and stirred slurry solution of AlCl₃ (0.64 g, 4.76 mmol) in CH₂Cl₂ (20 mL). After 15 min, vinylidene chloride (0.38 mL, 0.46 g, 4.76 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was then poured over ice and was acidified using 1 N HCl (15 mL). Stirring was continued for 20 min and the product was extracted with CH₂Cl₂ (3×). The combined organic extracts were dried over Na₂SO₄ and concentrated in vacuo to give 3,3-dichloro-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one (0.88 g, 68% ) as a light yellow oil: ¹H-NMR (CDCl₃, 300 MHz)δ8.38, d, J=8.4, 1H). 7.40 (d, J=8.4, 1H), 7.10 (s, 1H); R_(f)=0.51 (4:1 Hex:EtOAc).

Intermediate Q 3,3-dianilino-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one

A solution of aniline (1.01 mL, 11.1 mmol) in TEA (1.55 mL, 11.1 mmol) was added slowly to a cooled (0° C.) and stirred solution of 3,3-dichloro-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one (1.0 g, 3.69 mmol) in dioxane (20 mL). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated in vacuo until most of the solvent was removed. The residue was diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with water, dried over Na₂SO₄ and concentrated in vacuo. Silica gel flash chromatography of the residue using 6:1EtOAc:Hex gave 3,3-dianilino-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one as pale yellow solid (0.69 g, 49%): LCMS RT: 3.81 min; MH⁺: 384.2.

Intermediate R 2-anilino-7-chloro-1-phenyl-2,3-dihydro-1,8-naphthyridin-4(1H)-one

A mixture of 3,3-dianilino-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one (0.08 g, 0.21 mmol) and NaH (0.009 g, 0.23 mmol) in THF (6 mL) was heated to 80° C. overnight. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Silica gel flash chromatography of the residue using 3:1 Hex:EtOAc provided 2-anilino-7-chloro-1-phenyl-2,3-dihydro-1,8-naphthyridin-4(1H)-one (49 mg, 68%) as an off-white solid: LC-MS RT: 2.56 min, MH⁺: 348.2. This transformation can be accomplished by using the combination of other aprotic solvents such as dioxane and DMF with other bases such as t-BuOK.

Intermediate S Ethyl 3-(2-chloro-6-methyl(3-pyridyl))-3-oxopropanoate

Ethyl 3-(2-chloro-6-methyl(3-pyridyl))-3-oxopropanoate was prepared by the general procedure described in the Journal of Medicinal Chemistry, 1986, 29, 2363. The product had: MH⁺: 242.1, LCMS RT: 2.33 and 3.06 min (keto-enol).

Intermediate T Ethyl (2Z)-2-[(2-chloro-6-methyl(3-pyridyl))carbonyl]-3,3-dimethylthio-prop-2-enoate

Cs₂CO₃ (24.0 g, 72.5 mmol) was added to a solution of ethyl 3-(2-chloro-6methyl(3-pyridyl))-3-oxopropanoate (7.0 g, 29 mmol) in THF (290 mL). The reaction mixture was cooled to −10° C. and after 15 min, CS₂ (8.7 mL, 145 mmol) was added. Stirring was continued for 2 h and MeI (4.5 mL, 72.5 mmol) was added. The reaction was slowly warmed to room temperature over 18 h and filtered. The filtrate was to concentrated in vacuo to provide ethyl (2Z)-2-[(2-chloro-6-methyl(3-pyridyl))carbonyl]-3,3-dimethylthioprop-2-enoate as a yellow oil that was used without purification. LCMS RT: 2.79 min, MH⁺: 345.8. A variety of alkyl halides can be used to quench the generated sulfur anion.

Intermediate U Ethyl (2E)-3,3-bis(phenylamino)-2-[(2chloro-6-methyl(3-pyridyl))carbonyl]prop-2-enoate

A solution of ethyl (2Z)-2-[(2-chloro-6-methyl(3-pyridyl))carbonyl]-3,3-dimethylthioprop-2-enoate (100. mg, 0.28 mmol) and aniline (0.076 mL, 0.83 mmol) in THF (1.4 mL) was heated at reflux for 18 h. The reaction was cooled to room temperature and concentrated in vacuo. Silica gel flash chromatography of the residue using 1:1 EtOAc:Hex provided ethyl (2E)-3,3-bis(phenylamino)-2-[(2-chloro-6-methyl(3-pyridyl))carbonyl]prop-2-enoate (55.6 mg, 44%): LCMS RT: 3.56 min, MH⁺: 436.3.

Intermediate V Ethyl 7-methyl-2-methylthio-4-oxo-1-phenylhydropyridino[2,3-b]-pyridine-3-carboxylate

Aniline (3.96 mL, 43.5 mmol) was added to a solution of ethyl (2Z)-2-[(2-chloro-6-methyl(3-pyridyl))carbonyl]-3,3-dimethylthioprop-2-enoate (5.13 g, 14.5 mmol) in DMSO (72.5 mL). The reaction solution was heated to 70° C. for 18 h and then cooled to room temperature. The solution was diluted with EtOAc, washed with water and brine, dried over Na₂SO₄, and concentrated in vacuo. Trituration of the resulting orange oil with Et₂O afforded some desired product as a yellow solid. Additional product was obtained by silica gel flash chromatography of the mother liquor using 1:1 EtOAc:Hex. The two purifications provided ethyl 7-methyl-2-methylthio-4-oxo-1-phenylhydropyridino[2,3-b]pyridine-3-carboxylate (2.87 g, 56%) as a yellow solid: LCMS RT: 2.85 min, MH⁺: 355.0.

Intermediate W Ethyl 7-methyl-4-oxo-1-phenyl-2-(phenylamino)hydro-pyridino[2,3-b]-pyridine-3-carboxylate

A solution of ethyl (2E)-3,3-bis(phenylamino)-2-((2-chloro-6-methyl(3-pyridyl))carbonyl)prop-2-enoate (85.0 mg, 0.195 mmol) and t-BuOK (67 mg, 0.60 mmol) in dioxane (2 mL) was heated at reflux for 48 h. The reaction was cooled to room temperature and concentrated in vacuo. Silica gel flash chromatography of the residue using 3:1 Hex:EtOAc to 100% EtOAc gave ethyl 7-methyl-4-oxo-1-phenyl-2-(phenylamino)hydropyridino[2,3-b]pyridine-3-carboxylate (39 mg, 49%) as a white solid: LCMS RT: 2.80 min, MH⁺ 400.0. This transformation can be accomplished by using the combination of other aprotic solvents such as DMF and THF with other bases such as NaH.

Intermediate X Ethyl 2-[(4-chlorophenyl)anilino]-7-methyl-4-oxo-1-phenyl-hydropyridino-[2,3-b]pyridine-3-carboxylate

KRMDS (0.5 M in toluene, 0.84 mL, 0.42 mmol) was added to a cooled (−78° C.) solution of 4-chloroaniline (71.4 mg, 0.560 mmol) in THF (0.70 mL). After 2 h, a solution of ethyl 7-methyl-2-methylthio-4-oxo-1-phenylhydropyridino[2,3-b]pyridine-3-carboxylate (100 mg, 0.28 mmol) in THF (0.70 mL) was added resulting in immediate formation of an orange solution. The reaction was slowly warmed to room temperature, stirred for 21 h, and quenched with saturated aqueous NH₄Cl. The aqueous solution was extracted with Et₂O (3×) and the combined organic extracts were washed with water and brine, dried over Na₂SO₄, and concentrated in vacuo. Silica gel flash chromatography of the residue using 1:1EtOAc:Hex gave ethyl 2-[(4-chlorophenyl)amino]-7-methyl-4-oxo-1-phenylhydropyridino[2,3-b]pyridine-3-carboxylate (30.0 mg, 25%) as a white solid:

LCMS RT: 2.98 min, MH⁺434.0.

Intermediate Y 5-Bromo-2-hydroxy-6-methyinicotinc acid

A solution of NaOBr was prepared by adding Br₂ (11.4 g, 3.66 mL, 71.3 mmol) to a cooled (0° C.) and stirred solution of NaOH (7.8 g, 196 mmol) in water (90 mL). This solution was warmed to room temperature and was then added to a solution of commercially available (Aldrich) 2-hydroxy-6-methylpyridine-3-carboxylic acid (10.0 g, 65.1 mmol) and NaOH (7.8 g, 196 mmol) in water (30 mL). After stirring for 5 min, the mixture was cooled to 0° C. and carefully acidified with conc. HCl. The precipitate was filtered and dried over MgSO₄ to afford 5-bromo-2-hydroxy-6-methylnicotinc acid (15.0 g, 99%): ¹H NMR (DMSO-d₆) 8.25 (s, 1H), 2.41 (s, 3H); MH⁺: 232.0. Elemental analysis calculated for C₇H₆BrNO₃: C, 36.23; H, 2.61; N, 6.04; Br, 34.44; Found: C, 36.07; H, 2.44; N, 5.91; Br, 34.43.

Intermediate Z (Same as Intermediate BA) 2,4-dichloro-6-methylnicotinic acid

A solution of commercially available (Maybridge) ethyl 2,4-dichloro-6-methylpyridine-3-carboxylate (1.0 g, 4.3 mmol) and NaOH (342 mg, 8.6 mmol) in water (1.7 mL) and MEOH (1.5 mL) was heated to 80° C. for 4 h. The mixture was acidified using 50% H₂SO₄ and filtered. The solid was washed with cold water and dried to give of 2,4-dichloro-6-methylpyridine-3-carboxylic acid (582 mg, 66%): LCMS RT: 0.70 min, MH+: 206.2.

Intermediate AA (Same as Intermediate BB) 3,3-dichloro-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one

The compound was prepared according to the procedure described for Intermediate BB below. LCMS RT: 3.13 min, MH⁺: 284.6.

Intermediate AB (Same as Intermediate BC) 3,3-dianilino-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one

The compound was prepared according to the procedure described for Intermediate BC below: LCMS RT: 3.06 min, MH⁺: 398.7.

Intermediate AC (2Z)-3-anilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-3-(isopropylanino)-2-propen-1-one

3,3-dichloro-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one (374.0 mg, 1.29 mmol) was dissolved in CH₂Cl₂ (5 mL) and cooled to 10° C. Aniline (120.0 mg, 1.29 mmol) and isopropylamine (76.5 mg, 1.29 mmol) were added dropwise as a mixture in 3 mL of 1,4-dioxane. TEA (0.897 mL, 6.45 mmol) was added and the reaction mixture was warmed to room temperature and left to stir for 2 h. The dioxane was removed in vacuo and the brown residue was partitioned between EtOAc and saturated aqueous NaHCO₃. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO₄ and concentrated in vacuo. Purification of the residue using Biotage silica gel chromatography eluting with 6:1 to 7:3 Hex:EtOAc provided (2Z)-3-anilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-3-(isopropylamino)-2-propen-1-one (45 mg, 10%) as an off-white solid: LCMS RT: 3.63 min, MH⁺: 368.2.

Intermediate AD 4-Nitrophenyl 2-{[3-(trifluoromethyl)phenyl]amino}nicotinate

To a warmed (40° C. ) suspension of niflumic acid (10.0 g, 35.4 mmol) and 4-nitrophenol (4.9 g, 35.4 mmol) in CH₂Cl₂ (80 mL) was added a suspension of EDCI (6.8 g, 35.4 mmol) in CH₂Cl₂ (20 mL). The reaction was stirred for 16 h, and then cooled to room temperature. The solution was quenched with water (50 mL), and the aqueous layer was extracted with CH₂Cl₂. The combined organic extracts were washed with water and dried over Na₂SO₄. The solvent was removed in vacuo, and the residue was purified by trituration with Hex:CH₂Cl₂ to afford 4-Nitrophenyl 2-{[3-(trifluoromethyl)phenyl]amino}nicotinate (4.5 g, 31%): LCMS RT: 4.03 min, MH⁺: 404.1.

Intermediate AE Ethyl 2-cyano-3-oxo-3-(2-{[3-(trifluoromethyl)phenyl]amino}-3-pyridinyl)propanoate

To a stirred mixture of NaH (524 mg, 21.8 mmol) in toluene (20 mL) was added dropwise ethyl cyanoacetate (3.7 g, 32.7 mmol, 3.5 mL). The slurry was stirred for 1 h and then 4-nitrophenyl 2-{[3-(trifluoromethyl)phenyl]amino}nicotinate (4.4 g, 10.9 mmol) was added. The reaction mixture was stirred for 1 h and then quenched with water (20 mL). CH₂Cl₂ (30 mL) was added and the layers were partitioned. The organic layer was washed with brine (2×) and dried over Na₂SO₄. The solvent was removed in vacuo and the residue was purified by silica gel flash chromatography (5:1 to 2:1 Hex:EtOAc) to afford 3 Ethyl 2-cyano-3-oxo-3-(2-{[3-(trifluoromethyl)phenyl]amino}-3-pyridinyl)propanoate. (6 g, 87%): LCMS RT: 2.83 min, MH⁺: 378.0.

Intermediate AF 2-Amino-1-[3-(trifluoromethyl)phenyl]-1,8-naphthyridin-4(1H)-one

Ethyl 2-cyano-3-oxo-3-(2-{[3-(trifluoromethyl)phenyl]amino}-3-pyridinyl) propanoate (2.0 g, 5.3 mmol) was heated to 120° C. in a mixture of conc. HCl (4 mL) and glacial acetic acid (2 mL) for 3 h. The reaction mixture was cooled to room temperature, and neutralized by slow addition of NaOH pellets. The mixture was extracted with CH₂Cl₂ (3×). The combined organic extracts were washed with saturated aqueous NaHCO₃ (10 mL) and brine (10 mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified by prep-HPLC (YMC-Pack Pro C18 Column, 150×20 mm I.D.; 30-70% CH₃CN in water, 20 min.) to afford 2-Amino-1-[3-(trifluoromethyl)phenyl]-1,8-naphthyridin-4(1H)-one (880 mg, 55%): LCMS RT: 2.03 min, MH⁺: 306.3.

Intermediate AG 7-chloro-6-fluoro-2-(isopropylamino) 1-phenyl-1,8-naphthyridin-4(1H)-one

(2Z)-3-Anilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-3-(isopropylamino)-2-propen-1-one (40.0 mg, 0.109 mmol) was dissolved in 4 mL of DMF. NaH (8.70 mg, 0.217 mmol, 60% dispersion in oil) was added and the reaction was heated to 85° C. under argon for 2 h. The reaction mixture was cooled to room temperature and diluted with water and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO₄ and concentrated in vacuo. Purification of the residue using Biotage silica gel chromatography eluting with 100% EtOAc to 95:5 EtOAc:MeOH provided 7-chloro-6-fluoro-2-isopropylamino)-1-phenyl-1,8-naphthyridin-4(1H)-one (21 mg, 64%) as a white solid: LCMS RT: 2.57 min, MH⁺: 332.2.

Intermediate AH 2-anilino-7-chloro-6-fluoro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

A solution of LTMP [freshly prepared at 0° C. from tetramethylpiperidine (227.2 mg, 1.62 mmol), TMEDA (188.3 mg, 1.62 mmol) and n-BuLi (1 mL, 1.62 mmol)] in THF (5 mL) was added to a cooled (−40° C.) and stirred solution of 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (200 mg, 0.54 mmol) in THF (10 mL). The reaction mixture was warmed to 0° C., for 1 h and then re-cooled to −40° C. MeI (766 mg, 5.35 mmol) was added and the reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction was quenched carefully with water (50 mL) and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Silica gel flash chromatography of the residue using 1:1 EtOAc:Hex afforded 2-anilino-7-chloro-6-fluoro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (184 mg, 88%) as a white solid: LCMS RT: 2.74 min, MH⁺: 380.3. This transformation can also be accomplished by using other amide bases such as LDA.

Intermediate AI 2-anilino-7-chloro-6-fluoro-1-phenyl-5-(trifluoroacetyl)-1,8-naphthyridin-4(1H)-one

A solution of LTMP [freshly prepared at 0° C. from tetramethylpiperidine (154 mg, 1.10 mmol), TMEDA (127.8 mg, 1.10 mmol) and n-BuLi (0.688 mL, 1.10 mmol)] in THF (5 mL) was added to a cooled (−40° C.) stirred solution of 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.273 mmol) in THF(10 mL). The reaction was stirred for 1 h and then cooled to −78° C. Methyl trifluoroacetate (350 mg, 2.74 mmol) was added and stirring was continued for 2 h. The reaction was quenched carefully with water (50 mL), warmed to room temperature and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Silica gel flash chromatography of the residue using 3:1 Hex:EtOAc gave 2-anilino-7-chloro-6-fluoro-1-phenyl-5-(trifluoroacetyl)-1,8-naphthyridin-4(1H)-one (71 mg, 56%) as a light yellow solid: LCMS RT: 3.43 min, MH⁺: 462.3. The anion generated from LTMP deprotonation can be quenched with other electrophiles including carbon dioxide and 4-nitrophenyl acetate.

Intermediate AJ 7-chloro-5-methyl-2-[methyl(phenyl)amino]-1-phenyl-1,8-naphthyridin-4(1H)-one

MeI (0.10 mL, 228 mg, 1.6 mmol) was added to a stirred suspension of K₂CO₃ (23.5 mg, 0.17 mmol) and 2-anilino-7-chloro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (50 mg, 0.14 mmol) in THF (3 mL). The suspension was heated to 40° C. and stirred was overnight. The reaction was quenched with water (5.0 mL) and extracted with EtOAc. The combined organic extracts were dried over Na₂SO₄ and concentrated in vacuo. Recrystallization of the residue using EtOAc afforded 7-chloro-5-methyl-2-[methyl(phenyl)amino]-1-phenyl-1,8-naphthyridin-4(1H)-one (18 mg, 35%): LCMS RT: 2.24 min, MH⁺: 376.6, R_(f)=0.76 (4:1 Hex:EtOAc).

Intermediate AK N-(7-chloro-5-methyl-4-oxo-1-phenyl-1,4-dihydro-1,8-naphthyridin-2-yl)-N′-(4-fluorophenyl)-N-phenylurea

4-Fluorophenyl isocyanate (45.0 mg, 0.33 mmol) was added to a stirred solution of 2-anilino-7-chloro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.276 mmol) in CH₂Cl₂ (3 mL). After 16 h, an additional equivalent of 4-fluorophenyl isocyanate (45.0 mg) was added, and the reaction stirred for an additional 16 h. The reaction was concentrated in vacuo and the residue was dissolved in EtOAc. The solution was washed with 1 N HCl, dried over MgSO₄, and concentrated in vacuo. Purification of the residue using reverse phase prep-HPLC afforded N-(7-chloro-5-methyl-4-oxo-1-phenyl-1,4-dihydro-1,8-naphthyridin-2-yl)-N′-(4-fluorophenyl)-N-phenylurea (2.2 mg, 1.6%): LCMS RT: 3.47 min, MH⁺: 499.1, R_(f)=0.52 (1:1 EtOAc:Hex).

Intermediate AL 2-anilino-7-chloro-3-iodo-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

K₂CO₃ (210 mg, 1.52 mmol) and 12 (390 mg, 1.52 mmol,) were added to a solution 2-anilino-7-chloro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (500 mg, 1.38 mmol) in DMF (10 mL). The mixture was stirred for 30 min and then poured into an aqueous solution of saturated Na₂S₂O₃ (10 mL). The aqueous solution was extracted with EtOAc. The combined organic extracts were dried over MgSO₄, and concentrated in vacuo. Silica gel flash chromatography of the residue using 4:1 to 1:1 Hex:EtOAc afforded 2-anilino-7-chloro-3-iodo-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (380 mg, 56%): LCMS RT: 3.45 min, MH⁺: 488.2, R_(f)=0.5 (2:1 Hex:EtOAc).

Intermediate AM 2-anilino-7-chloro-6-fluoro-5-(1-hydroxypropyl)-1-phenyl-1,8-naphthyridin-4(1H)-one

A −40° C. solution of 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.274 mmol) in THF (10 mL) was treated with LTMP (1.10 mmol, freshly prepared by mixing 2,2,6,6-Tetramnethyl piperidine and n-BuLi at 0° C. for 30 min.). The mixture was then allowed to warm to 0° C. for 2 h. The reaction mixture was cooled to −30° C. and propionaldehyde (159 mg, 2.74 mmol) was added. The reaction was stiffed at −30° C. for 2 h before it was slowly quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography to afford 2-anilino-7-chloro-6-fluoro-5-(1-hydroxypropyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (120 mg, 97%) as a white solid: LCMS RT: 3.14 min, MH⁺: 424.2. Other electrophiles such as disulfide may be used to quench the anion.

Example 1 2-anilino5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

A solution of 2-anilino-7-chloro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (95.0 mg, 0.263 mmol), TEA (0.65 mmol), and 10% Pd/C in EtOAc (2.5 mL) and EtOH (2.5 mL) was stirred under H₂ (1 atm) for 3.5 h. The reaction mixture was filtered through a pad of Celite using EtOH and EtOAc to rinse. The combined filtrates were concentrated in vacuo, and purified with Biotage silica gel chromatography using 1:1 EtOAc:Hex to afford 2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (84 mg, 98%) as a pale yellow solid. LCMS RT: 2.26 min, MH⁺: 328.4, R_(f)=0.1 (1:1 EtOAc:Hex),

Example 2 5-Methyl-7-morpholin-4-yl-1-phenyl-2-phenylamino-1H-[1,8]-naphthyridin-4-one

A mixture of 7-chloro-5-methyl-1-phenyl-2-phenylamino-1H-[1,8]naphthyridin-4-one (68.3 mg, 0.189 mmol) and morpholine (0.05 mL, 0.48 mmol) in dioxane (3 mL) was heated to 80° C. for 2 d. The reaction was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na₂SO₄, and concentrated in vacuo to give 5-methyl-7-morpholin-4-yl-1-phenyl-2-phenylamino-1H-[1,8]naphthyridin-4-one (67 mg, 92%) as yellow solid: LCMS RT: 2.33 min, MH⁺: 413.4, R_(f)=0.49 (EtOAc).

Example 3 5-Methyl-1-phenyl-2,7-bis-phenylamino-1H-[1,8]naphthyridin-4-one

A mixture of 7-chloro-5-methyl-1-phenyl-2-phenylamino-1H-[1,8]naphthyridin-4-one (15.1 mg, 0.042 mmol), aniline (2 drops), Pd(OAc)₂ (0.27 mg, 0.001 mmol), Cs₂CO₃ (19.5 mg, 0.06 mmol), and BINAP (1.68 mg, 0.003 mmol) in THF (0.5 mL) was heated at reflux for 16 h. The reaction was quenched with water and extracted with EtOAc (3×). The combined organic extracts were washed brine, dried over Na₂SO₄, and concentrated in vacuo to give 5-methyl-1-phenyl-2,7-bis-phenylamino-1H -[1,8]naphthyridin-4-one (6.0 mg, 38%): LCMS RT: 2.57 min, MH⁺: 419.5, R_(f)0.18 (EtOAc).

Example 4 2-anilino-1,7-diphenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one

A solution of 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (10.0 mg, 0.241 mmol), Ph₃P (6.00 mg, 0.024 mmol) and phenylboronic acid (36.0 mg, 0.290 mmol) in DME was treated with 2M K₂CO₃ (0.482 mL, 0.964 mmol) and Pd(OAc)₂ (1.35 mg, 0.006 mmol). The mixture was heated at reflux for 24 h. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. Purification by preparative HPLC (10% CH₃CN in water with 0.1% TFA to 95% CH₃CN in water, 10 mL/min, 10 min) provided 2-anilino-1,7-diphenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (45.0 mg, 41%): LCMS RT: 3.76 min, MH⁺: 458.4.

Example 5 2-anilino-7-benzyl-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

To a solution of 2-anilino-7-chloro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.277 mmol) in THF was added Ni(dppp)Cl₂ (37.0 mg, 0.069 mmol). After stirring for 5 min, benzylmagnesium chloride (2M, 1.45 mL, 2.90 mmol) was added dropwise via syringe and the mixture was allowed to stir for 24 h. The mixture was quenched with 1 N HCl and extracted with EtOAc. The organic layer was washed brine, dried over MgSO₄, and concentrated in vacuo. Purification by preparative HPLC (10% MeNC in water with 0.1% TFA to 95% CH₃CN in water, 10 mL/min, 10 min) provided 2-anilino-7-benzyl-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (47.3 mg, 41%): LCMS RT: 2.85 min, MH⁺: 418.3.

Example 6 Ethyl {[7-anilino-5-oxo-8-phenyl-4-(trifluoromethlyl)-5,8-dihydro-1,8-naphthyridin-2-yl]sulfanyl}acetate

NaH (60% dispersion in oil, 18.0 mg, 0.434 mmol) was added to a cooled (0° C.) and stirred solution of ethyl mercaptoacetate (0.05 mL, 0.434 mmol) in DMF. After 0.5 h, 2-anilino-7-chloro-1-phenyl-5-trifluoromethyl-1,8-naphthyridin-4(1H)-one (150.0 mg, 0.361 mmol) was added as a solid in a single portion. The mixture was allowed to warm to room temperature and was stirred for 24 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. Purification by preparative HPLC (10% CH₃CN in water with 0.1% TFA to 95% CH₃CN in water, 10 mL/min, 10 min) provided ethyl {[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-1,8-naphthyridin-2-yl]sulfanyl}acetate (50 mg, 53%): LCMS RT: 3.91 min, MH⁺: 500.2, R_(f)=0.24 (1:1 EtOAc:Hex).

Example 7 {[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-1,8-naphthyridin-2-yl]sulfanyl}acetic acid

NaOH (160 mg, 4.0 mmol) was added to a stirred solution of ethyl {[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-1,8-naphthyridin-2-yl]sulfanyl }acetate (30.0 mg, 0.060 mmol) in aqueous EtOH (10 mL EtOH in 4 mL H₂O). The mixture was allowed to stir for 4 h and was then concentrated in vacuo. The reaction was acidified with 1N HCl and extracted with CH₂Cl₂. The organic layer was dried over MgSO₄, and concentrated in vacuo. Purification by preparative HPLC (10% CH₃CN in water with 0.1% TFA to 95% CH₃CN in water, 10 mL/min, 10 min) provided {[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-1,8-naphthyridin-2-yl]sulfanyl }acetic acid (19.0 mg, 66%): LCMS RT: 2.50 min, MH⁺: 472.1

Example 8 2-anilino-1-phenyl-7-(1-piperidinyl)-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one

To a solution of 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (100.0 mg, 0.241 mmol) in dioxane (2.5 mL) was added piperdine (40.9 mg, 0.481 mmol). The mixture was left to stir at 80° C. overnight. The mixture was cooled to room temperature, poured into 1N HCl (1 mL) and extracted with CH₂Cl₂. The organic extracts were combined, washed with saturated aqueous NaHCO₃, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by Biotage silica gel chromatography (1:1 EtOAc:Hex) to provide 2-anilino-1-phenyl-7-(1-piperidinyl)-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (89.5 mg, 80%) as a pale yellow solid: LCMS RT: 2.76 min, MH⁺: 465.5.

Example 9 2-anilino-7-[2-(2-oxo-1-pyrrolidinyl)ethoxy]-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one

NaH (60% dispersion, 20.0 mg, 0.514 mmol) was added to a cooled (0° C.) and stirred solution of 1-(2-hydroxyethyl)-2-pyrrolidinone (0.06 mL, 0.514 mmol) in DMF. After 0.5 h, 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (178 mg, 0.428 mmol) was added as a solid in a single portion and the mixture was heated to 130° C. for 48 h. After cooling to room temperature the mixture was quenched with saturated aqueous NH₄Cl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. Purification by preparative HPLC (10% CH₃CN in water with 0.1% TFA to 95% CH₃CN in water, 10 mL/min, 10 min) provided 2-anilino-7-[2-(2-oxo-1-pyrrolidinyl)ethoxy]-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (0.047 g, 64%): LCMS RT: 2.40 min, MH⁺: 509.2. This transformation can be accomplished by using other aprotic solvents such as DMSO, THF and dioxane with temperatures appropriate for these solvents. Commercially available alkoxides can also be used in the absence of base.

Example 10 2-anilino-5-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one

A solution of LDA (38.2 mmol, freshly prepared from n-BuLi and diisopropylamine) in THF (53 mL) was added to a cooled (−78° C.) and stirred suspension of 2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (2.50 g, 7.64 mmol) in THF (100 mL). The resulting mixture was stirred for 1 h, and then oxygen gas was bubbled, through a fritted glass tube, into the bottom of the reaction vessel. The mixture was stirred overnight, with continued bubbling of oxygen with slow warming to room temperature. The reaction was quenched with water and 1M HCl (5 mL), and then extracted with CH₂Cl₂. The organic phase was dried over Na₂SO₄ and concentrated in vacuo to afford an orange solid which was recrystalized from EtOAc to obtain 2-anilino-5-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (1.38 g, 53%): LCMS RT: 2.01 min, M⁺: 344.3, R_(f)=0.22 (95:5 CH₂Cl₂:MeOH).

Example 11 2-anilino-1-phenyl-5-(1-piperazinylmethyl)-1,8-naphthyridin-4(1H)-one

A solution of 2-anilino-5-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (180 mg, 0.52 mmol), N,N-diisopropylethylamnine (0.10 mL, 0.52 mmol) and SOCl₂ (0.12 mL, 1.57 mmol) in CH₂Cl₂ (7 mL) was stirred at room temperature for 2 h. Excess SOCl₂ and solvent were removed in vacuo to afford a brownish solid. Crude 2-anilino-5-(chloromethyl)-1-phenly-1,8-naphthyridin-4(1H)-one was used without further purification: LCMS RT: 2.50 min, MH⁺: 362.3.

DMF (1 mL) was added to a stirred suspension of crude 2-anilino-5-(chloromethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (15.0 mg, 0.041 mmol), N,N-diisopropylethylamine (0.036 mL, 0.21 mmol), and piperazine (36 mg, 0.21 mmol) in 1,4-dioxane (2 mL). The solution was heated to 50° C. overnight, cooled to room temperature and concentrated in vacuo. Reverse phase preparative HPLC (0.1% TFA in CH₃CN and water) of the residue gave 2-anilino-1-phenyl-5-(1-piperazinylmethyl)-1,8-naphthyridin-4(1H)-one (8.0 mg, 37%) as the TFA salt: LCMS RT: 0.71 min, MH⁺: 412.2.

Example 12 5-Methyl-1-phenyl-2-phenylamino-7-piperazin-1-yl-1H-[1,8]naphthyridin-4-one

A mixture of 5-methyl-1-phenyl-2-phenylamino-7-piperazin-1-yl-1H-[1,8]naphthyridin-4-one (22.6 mg, 0.055 mmol) and MsCl (0.083 mmol, 0.006 mL) in CH₂Cl₂ (0.8 mL) was stirred at room temperature overnight at which time the solvent was removed in vacuo. The resulting residue was purified by prep-TLC to give 7-(4-methanesulfonyl-piperazin-1-yl)-5-methyl-1-phenyl-2-phenylamino-1H-[1,8]naphthyridin-4-one (3.4 mg, 6%): LCMS RT: 2.36 min, MH⁺: 490.3.

Example 13 5-methyl-1-phenyl-2-phenylamino-7-(4-propionyl-piperazin-1-yl)-1H-[1,8]naphthyridin-4-one

A mixture of 5-methyl-1-phenyl-2-phenylamino-7-piperazin-1-yl-1H-[1,8]naphthyridin-4-one (21.0 mg, 0.052 mmol), propionic acid (0.004 mL, 0.055 mmol), EDCI (11.9 mg, 0.062 mmol), DMAP (7.6 mg, 0.062 mmol), and NMM (0.006 mL, 0.062) in CH₂Cl₂ (0.8 mL) was stirred at room temperature overnight. The reaction was diluted with water and extracted with CH₂Cl₂. The combined organic extracts were washed with 0.5 N HCl and brine and concentrated in vacuo. The residue was purified by prep-TLC eluting with 100% EtOAc to give 5-methyl-1-phenyl-2-phenylamino-7-(4-propionyl-piperazin-1-yl)-1H-[1,8]naphthyridin-4-one (9.0 mg, 37%): LCMS RT: 2.29 min, MH⁺: 468.3.

Example 14 2-anilino-5-bromo-6-fluoro-7-methoxy-1-phenyl-1,8-naphthyridin-4(1H)-one

A solution of LTMP [freshly prepared at 0° C. from tetramethylpiperidine (785.4 mg, 5.6 mmol), TMEDA (651 mg, 5.6 mmol) and n-BuLi (3.5 mL, 5.6 mmol)] in THF (10 mL) was added to a cooled (40° C.) stirred solution of 2-anilino-6-fluoro-7-methoxy-1-phenyl-1,8-naphthyridin-4(1H)-one (507 mg, 104 mmol) in THF (20 mL). The reaction mixture was warmed to room temperature. After 1 h, the mixture was cooled to −30° C. and 1,2-dibromotetrachloroethane (457 mg, 1.4 mmol) was added. After 30 min, water (50 mL) was added slowly, and then the reaction was warmed to room temperature and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Silica gel flash chromatography of the residue using EtOAc afforded 2-anilino-5-bromo-6-fluoro-7-methoxy-1-phenyl-1,8-naphthyridin-4(1H)-one (101 mg, 16%) as a light yellow solid: LCMS RT: 2.75 min, MH⁺: 440.3.

Example 15 7-Methyl-1-phenyl-2-(phenylanino)hydropyridino[2,3-b]pyridin-4-one

Ethyl 7-methyl-4-oxo-1-phenyl-2-(phenylamino)hydropyridino[2,3-b]pyridine-3-carboxylate (67 mg, 0.17 mmol) was dissolved in a 2:1 HCl:AcOH solution (8.5 mL). The reaction was heated to 120° C. for 5 h then cooled to room temperature. The aqueous solution was washed with Et₂O and then neutralized with 2 N NaOH and extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaHCO₃ and brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo to provide 7-methyl-1-phenyl-2-(phenylamino)hydropyridino[2,3-b]pyridin-4-one (40 mg, 72%): LCMS RT: 2.28 min, MH⁺: 328.4.

Example 16 2-anilino-5-chloro-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

A mixture of 3,3-dianilino-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one (100 mg, 0.25 mmol) and t-BuOK (42 mg, 0.38 mmol) in anhydrous dioxane (4 mL) was heated to 80° C. for 4 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The solution was washed with water and brine, dried over MgSO₄, and concentrated in vacuo. Silica gel flash chromatography of the residue using 1:1 EtOAc:Hex gave 2-anilino-5-chloro-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (13 mg, 14%): LCMS RT: 2.47 min, MH⁺: 362.6. 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one was also isolated (68 mg, 75%): LCMS RT: 2.24 min, MH⁺: 362.6. This transformation can be accomplished by using the combination of other aprotic solvents such as DMF and THF with other bases such as NaH.

Example 17 Ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine carboxylate

2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (200 mg, 0.55 mmol), DPPP (12 mg, 0.030 mmol), Pd(OAc)₂ (6.0 mg, 0.028 mmol), and Cs₂CO₃ (114 mg, 0.42 mmol) was dissolved in a 1:1 mixture of EtOH (3 mL)/DMF (3 mL). A balloon filled with CO was attached to the flask and the solution was stirred vigorously. The solution was saturated with CO by evacuating the flask followed by back filling the flask with CO. This was repeated 3 times before heating the solution to 70° C. After 4 h of stirring all of the starting material had been consumed and the reaction was cooled to room temperature. The solution was diluted with EtOAc and was washed with water. The organic layer was collected, dried over Na₂SO₄, and concentrated in vacuo. The crude solid was triturated with Et₂O, filtered and dried to give ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylate as a light brown solid (900 mg, 81%): LCMS RT: 2.63 min, MH⁺: 404.4

Example 18 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxamide

A suspension of ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylate (50 mg, 0.12 mmol), and NH₄Cl (10 mg, 0.19 mmol) in concentrated NH₃ (3 mL) and MeOH (8 drops) was stirred for 16 h at room temperature. The solid was collected by filtration washing with water. Trituration with Et₂O, provided 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxamide as a yellow solid (32 mg, 71%): LCMS RT: 1.93 min, MH⁺: 375.3. This transformation can also be accomplished using EDCI/HOBT coupling with NH₃.

Example 19 7-anilino-N-methoxy-N,4-dimethyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxamide

7-anilino-4-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylic acid (50 mg, 0.14 mmol), N,O-dimethylhydroxylamine hydrochloride (39 mg, 0.40 mmol), HOBT (28 mg, 0.21 mmol), EDCI (40 mg, 0.21 mmol) were dissolved in CH₂Cl₂ (3 mL). To this solution was added TEA (78 uL, 0.56 mmol). The reaction was stirred for 1 h and was diluted with CH₂Cl₂, washed with 0.5N HCl, saturated NaHCO₃, and brine. The organic layer was collected, dried over Na₂SO₄, and concentrated in vacuo. The solid obtained was triturated with Et₂O and dried to give 7-anilino-N-methoxy-N,4-dimethyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxamide as a light yellow solid (34 mg, 59%): LCMS RT: 2.28 min, MH⁺: 415.2. This transformation can also be accomplished by coupling the appropriate amine with the corresponding acid chloride.

Example 20 7-acetyl-2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

To a suspension of 7-anilino-N-methoxy-N,4-dimethyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxamide (100 mg, 0.24 mmol) in THF (5 mL) at 0° C. was added MeMgBr (3M in Et₂O, 322 uL, 0.97 mmol). The suspension became a red solution. As the reaction proceeded the solution lost its red color. After 1 h the reaction was quenched with saturated NH₄Cl, diluted with EtOAc, and washed with brine. The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The crude residue was purified by a Biotage silica gel chromatography using EtOAc to afford 7-acetyl-2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one as a light yellow solid (65 mg, 74%): LCMS RT: 2.63 min, MH⁺: 370.4.

Example 21 2-anilino-7-(butylsulfonyl)-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one

To a solution of montmorillonite K10(107.5 mg) in CHCl₃ was added 13 uL of water. 2-anilino-7-(butylsulfanyl)-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (25 mg, 0.06 mmol) was then added followed by oxone (85.2 mg, 0.14 mmol). The reaction was allowed to stir for 24 h at room temperature. After 24 h the solution was bright bluish-green in color and was filtered and washed with copious amounts of CHCl₃. The filtrate was then concentrated in vacuo. Silica gel flash chromatography using 3:1 Hex:EtOAc provided 2-anilino-7-(butylsulfonyl)-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one as a yellow oil (13.8 mg, 46%): LCMS RT: 3.14, MH⁺502.2.

Example 22 N-[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-1,8-naphthyridin-2-yl] methanesulfonamide

To a solution of 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (100 mg, 0.241 mmol) in DMSO (5 mL) was added methyl sulfonamide and K₂CO₃ (76.5 mg, 0.554 mmol). The reaction was stirred at 120° C. for 24 h. The reaction was then cooled to room temperature, quenched with water and extracted with Et₂O. The organic layers were dried over MgSO₄, and concentrated in vacuo. The crude residue was then passed through a plug of silica gel eluting with 1:1 Hex:EtOAc to 9:1 CH₂Cl₂:MeOH to afford N-[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-1,8-naphthyridin-2-yl]methanesulfonamide as a white solid (4.4 mg, 4%): LCMS RT: 2.45, MH⁺: 475.2.

Example 23 7-aniline-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carbaldehyde

2-anilino-6-fluoro-7-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.277 mmol) was dissolved in 4.5 mL CHCl₃. MnO₂(311 mg, 3.05 mmol) was added and the reaction was heated to 70° C. under argon for 3 d. The reaction mixture was filtered through celite and concentrated in vacuo. Purification by silica gel flash chromatography eluting with 3:1 to 100:0 EtOAc:Hex provided 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carbaldehyde (15 mg, 15%) as a white solid: LCMS RT: 2.18 min, MW: 360.2.

Example 24 7-amino-2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

Pd/C (30 mg, 1.75 mmol, 10%) was added to a 25 mL round bottom flask and was blanketed with argon. 7-(allylamino)-2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (150 mg, 0.392 mmol) was dissolved in EtOH (2 mL) and was added to the Pd/C followed by methane sulfonic acid (0.041 mL, 0.63 mmol). The reaction was heated to 80° C. for 3 d at which time it was cooled to room temperature, diluted with EtOAc and filtered through celite. The filtrate was concentrated in vacuo and the residue was purified by Biotage silica gel chromatography eluting with 100% EtOAc to provide 7-amino-2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (182 mg, 41%) as a yellow solid: LCMS RT: 2.01 min, MH⁺: 343.3.

Example 25 2-anilino-7-(hydroxymethyl)-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

To a 0° C. suspension of ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylate (100.0 mg, 0.25 mmol) in THF (2.5 mL) was added LAH (0.750 mmol, 1M in THF) dropwise over 10 min. After 5 min. the reaction was slowly quenched with EtOAc (10 mL), was left to stir for 15 min and was concentrated in vacuo. The residue was taken up in CH₂Cl₂ (10 mL) and 1N HCl (5 mL) and was left to stir for 30 min. The layers were separated and the aqueous layer was extracted with CH₂Cl₂. The combined organic extracts were washed with brine, dried over MgSO₄, and concentrated in vacuo. Trituation with Et₂O provided 2-anilino-6-fluoro-7-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (55.2 mg, 61%) as a tan solid: LCMS RT: 2.01 min, MH⁺: 362.3.

Example 26 2-anilino-7-[(4-methoxyphenoxy)methyl]-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

2-anilino-6-fluoro-7-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (62 mg, 0.175 mmol) was dissolved in CH₂Cl₂ (1.2 mL). 4-methoxyphenol (22 mg, 0.175 mmol) was added followed by Ph₃P (91.8 mg, 0.35 mmol), and ADDP (88.31 mg, 0.35 mmol). The reaction was left to stir overnight at room temperature under argon. Hexanes (5 mL) were added and the reaction was filtered. The filtrate was concentrated in vacuo. Purification of the residue using Biotage silica gel chromatography eluting with 7:3 to 9:1 EtOAc:Hex provided 2-anilino-6-fluoro-7-[(4-methoxyphenoxy)methyl]-1-phenyl-1,8-naphthyridin-4(1H)-one (30.0 mg, 37%) as a white solid: LCMS RT 2.87 min, MH⁺: 464.2.

Example 27 7-ethoxy-5-ethyl-2-[methyl(phenyl)amino]-1-phenyl-1,8-naphthyridin-4(1H)-one

And Example 28 2-anilino-7-ethoxy-5-ethyl-3-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

And Example 29 7-ethoxy-5-ethyl-3-methyl-2-[methyl(phenyl)amino]-1-phenyl-1,8-naphthyridin-4(1H)-one

To a suspension of 2,2,6,6-tetramethylpiperidine (153 mg, 0.18 mL, 1.08 mmol) in THF (10 mL) at 0° C., was added n-BuLi via syringe (1.6 M, 0.68 mL, 1.08 mmol) and TMEDA. The reaction mixture was stirred for 1 h under argon. The reaction mixture was cooled to −60° C. using an acetone/dry ice bath and 2-anilino-7-ethoxy-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.269 mmol) was added via syringe as a solution in THF (5 mL). The mixture was stirred for 1 h. MeI was added via syringe and the reaction was allowed to warm to room temperature and stirred for 18 h. A saturated aqueous solution of NH₄Cl (20 mL) and EtOAc (20 mL) was added, and the organic layer was separated, dried over MgSO₄ and concentrated in vacuo. The residue was purified by silica gel flash chromatography using 7:3 to 100:0 EtOAc:Hex to give 3 products as follows:

Example 27: (35 mg, 32%), Example 28: (11 mg, 10%), Example 29: (16 mg, 14%).

Example 30 2-anilino-6-fluoro-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one

To 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.273 mmol) in THF (5 mL) was added Pd(PPh₃)₄ (13 mg, 0.001 mmol) and methyl zinc chloride (2M, 0.819 mL, 1.64 mmol) and the reaction was heated to 75° C. for 18 h. The reaction was then cooled to room temperature and poured into a solution of EDTA in water (2.5 g/20 mL) and extracted with Et₂O. The organic layer was washed with brine and concentrated in vacuo. The residue was then taken up in MeOH and filtered. The filtrate was concentrated in vacuo to give 2-anilino-6-fluoro-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (83.0 mg, 89%): LCMS RT: 2.43 min, MH⁺: 346.4.

Example 31 Methyl (2E)-3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)-2-propenoate

To a suspension of 2-anilino-6-bromo-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (41 mg, 0.1 mmol) in DMF (2.0 mL) were successively added Pd(OAc)₂ (0.70 mg, 0.003 mmol), Ph₃P (5.2 mg, 0.02 mmol), TEA (0.03 mL) and methyl acrylate (17.2 mg, 0.2 mmol). The suspension was heated at 120° C. in a sealed tube for 64 h. The residue obtained after concentration in vacuo was washed with water and extracted with EtOAc. The organic layer was dried over MgSO₄ and concentrated in vacuo. Purification by prep-HPLC provided methyl (2E)-3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)-2-propenoate (10.0 mg, 24%): LCMS RT: 2.61 min, MH⁺: 412.3, R_(η)=0.26 (1:1 EtOAc:Hex).

Example 32 (2E)-3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)-2-propenoic acid

To a suspension of 2-anilino-6-[(E)-3-methoxy-3-oxo-1-propenyl]-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (10 mg, 0.025 mmol) in CH₃CN (2.0 mL) was added 1N NaOH (2.0 mL). The suspension was stirred at room temperature for 18 h. The mixture was diluted with water (10 mL) and extracted with EtOAc. The organic layer was dried over MgSO₄ and concentrated in vacuo to afford (2E)-3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)-2-propenoic acid (6.2 mg, 63%): LCMS RT: 2.37 min, MHR: 398.3, R_(f)=0.51 (EtOAc).

Example 33 3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)propanoicacid

To a stirred suspension of 2-anilino-6-[(E)-3-hydroxy-3-oxo-1-propenyl]-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (40.0 mg, 0.100 mmol) in MeOH (2.0 mL), was added Pd/C (5.3 mg, 10% weight on carbon) under an argon atmosphere, followed by the addition of ammonia formate (19.0 mg, 0.30 mmol) in a single portion. The reaction mixture was heated at reflux for 2 h, cooled and filtered. The filtrate was diluted with water (10 mL) and extracted with EtOAc. The organic layer was dried over MgSO₄ and concentrated in vacuo. The residue was washed with water and dried in vacuo to afford 3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)propanoicacid (34.5 mg, 86%): LCMS RT: 2.31 min, MH⁺: 400.4, R_(f)=0.61 (4:1 EtOAc:MeOH).

Example 34 2-anilino-6,7-dimethyl-1-phenyl-1,8-naphthyridin-4(1H)-one

Example 35 2-anilino-7-ethyl-1-(3-methylphenyl)-1,8-naphthyridin-4(1H)-one

A suspension of 2-anilino-6-bromo-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (203 mg, 0.5 mmol) in THF (10 mL) in an atmosphere of argon was cooled to −78° C. A solution of n-BuLi in hexanes (1.0 mL, 1.6 mmol, 1.6 M) was added and the suspension was stirred for 10 min at 0° C. until it became a clear solution. Excessive MeI (0.2 mL, 3.2 mmol) was added, and the reaction was stirred for another 10 min. The reaction was quenched with saturated aqueous NH₄Cl (2.0 mL) and water (10 mL) and the mixture was extracted with EtOAc. The organic layer was dried over MgSO₄ and concentrated in vacuo. The residue was purified by prep-HPLC to afford 2-anilino-6,7-dimethyl-1-phenyl-1,8-naphthyridin-4(1H)-one (55 mg, 32%): LCMS RT: 2.33 min, MH⁺: 342.4, R_(f)=0.39 (EtOAc). 2-anilino-7-ethyl-1-(3-methylphenyl)-1,8-naphthyridin-4(1H)-one (13.3 mg, 7.5%) was also obtained as a side product: LCMS RT: 2.54 min, MH⁺: 356.3, R_(f)=0.40 (EtOAc). Other electrophiles such as aldehydes, carbon dioxide, disulfides, trifluoroacetates acid chlorides and other alkyl halides can also be used to quench the generated aryl lithium.

Example 36 Ethyl 7-anilino-4-chloro-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyrdine-2-carboxylate

A suspension of ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylate (40.0 mg, 0.099 mmol) in anhydrous THF (10 mL) in an atmosphere of argon was cooled to −78° C. LiHMDS (5 mL, 5 mmol) was then added to the suspension, and the suspension was stirred for 2 h at 0° C. and then cooled to −78° C. and treated with CCl₂FCClF₂ (94 mg, 0.5 mmol). The reaction was stirred for another hour at 0° C. before being quenched with saturated aqueous NH₄Cl (2.0 mL) and water (10 mL) and extracted with EtOAc. The organic layer was dried over MgSO₄ and concentrated in vacuo. Purification of the residue by prep-HPLC provided Ethyl 7-anilino-4-chloro-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylate (13.2 mg, 31%): LCMS RT: 2.80 min, MH⁺: 437.1, R_(f)=0.78 (EtOAc).

Example 37 7-anilino-4-chloro-3-fluoro-N,N-diisopropyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxamide

LDA was made by adding n-BuLi (0.31 mL, 0.5 mmol, 1.6 M) to diisopropylamine (50 mg, 0.5 mmol) in THF (15 mL) at −15° C. A suspension of ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylate (40.0 mg, 0.915 mmol) in anhydrous THF (10 mL) in an atmosphere of argon was cooled to −78° C. LDA was added and the suspension was stirred for 2 h at 0° C. and then cooled to −78° C. and treated with CCl₂FCClF₂ (94 mg, 0.5 mmol). The reaction was stirred for another hour at 0° C. before being quenched with saturated aqueous NH₄Cl (2.0 mL) and water (10 mL). The aqueous solution was extracted with EtOAc and the organic layer was dried over MgSO₄ and concentrated in vacuo. Purification of the residue by prep-HPLC provided 7-anilino-3-bromo-4-chloro-N,N-diisopropyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxarnide (20 mg, 41%): LCMS RT: 3.02 min, MH⁺: 493.3, R_(f)=0.78 (EtOAc).

Example 38 2-[(4-Methylbenzyl)amino]-1-[3-(trifluoromethyl)phenyl]-1,8-naphthyridin-4(1H)-one

A mixture of 2-amino-1-[3-(trifluoromethyl)phenyl]-1,8-naphthyridin-4(1H)-one (50 mg, 0.16 mmol), CsCO₃ (160 mg, 0.49 mmol) and 4-methylbenzyl bromide (35 mg, 0.25 mmol) in THF (3 mL) was heated to 80° C. in a sealed tube for 16 h. The reaction was cooled to room temperature and quenched with water (3 mL). The mixture was extracted with CH₂Cl₂ (3×), and the combined organic extracts were dried with Na₂SO₄ and concentrated in vacuo. The residue was purified by prep-HPLC (YMC-Pack Pro C18 Column, 150×20 mm I.D.; first run: 20-80% CH₃CN in water, 11 min.; second run: 50-90% MeOH in water, 20 min.) to afford 2-[(4-Methylbenzyl)amino]-1-[3-(trifluoromethyl)phenyl]-1,8-naphthyridin-4(1H)-one (2.2 mg, 3%): LCMS RT: 2.75 min, MH⁺: 410.2.

The following specific examples are presented to illustrate the invention related to Formula (II) as described herein, but they should not be construed as limiting the scope of the invention in any way.

Intermediate BA 2,4-dichloro-6-methylnicotinic acid

A solution of commercially available (Maybridge) ethyl 2,4-dichloro-6-methylpyridine-3-carboxylate (1.0 g, 4.3 mmol) and NaOH (342 mg, 8.6 mmol) in water (1.7 mL) and MeOH (1.5 mL) was heated to 80° C. for 4 h. The mixture was acidified using 50% H₂SO₄ and then filtered. The solid collected was washed with cold water and dried to give of 2,4-dichloro-6- methylpyridine-3-carboxylic acid (582 mg, 66%): LCMS RT: 0.70 min, MH⁺: 206.2.

Intermediate BB 3,3-dichloro-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one

2,4-Dichloro-6-methylnicotinic acid (8.7 g, 43.0 mmol) was mixed with SOCl₂ (31 mL). The resulting mixture was heated to 80° C. for 2 h and concentrated in vacuo to give the acid chloride as yellow oil. The oil was then dissolved in CH₂Cl₂ (10 mL) and the solution was added to a cooled suspension of AlCl₃ (21.3 g, 160.0 mmol) in CH₂Cl₂ (50 mL) at 0° C. After 2 h at 0° C., vinylidene chloride (2.16 mL, 80.0 mmol) was added to the above suspension. The resulting mixture was then left to warm to room temperature and stirred overnight. The reaction mixture was poured into crushed ice and the resulting mixture was extracted with CH₂Cl₂. The combined organic layers were cooled to 0° C. and TEA (14.9 mL) was added. After 1 h of stirring, the organic layer was washed with 10% aqueous HCl (100 mL), water (200 mL), brine (100 mL), and dried over Na₂SO₄. Solvents were removed in vacuo and the residue was purified by passing it through a pad of silica gel with 15% EtOAc in Hex as the eluent to provide 3, 3-dichloro-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one (5.2 g, 46%): LCMS RT: 3.13 min, MH⁺: 284.6. Alternatively, the acid chloride could be prepared by using oxalyl chloride with a catalytic amount of DMF.

Intermediate BC 3,3-dianilino-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one

A solution of 3,3-dichloro-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one (5.2 g, 18.0 mmol) in 1,4-dioxane (25 mL) was cooled to 0° C. and aniline (5.1 mL, 55.0 mmol) and TEA (7.7 mL, 55.0 mmol) were added dropwise. The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 2 h. The solvents were removed in vacuo. The residue was purified by passing it through a pad of silica gel with EtOAc:Hex (1:5) as the eluent to provide 3,3-dianilino-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one (7.1 g, 99%): LCMS RT: 3.06 min, MH⁺: 398.7.

Intermediates BA1, BB1, BC1, BA2, BB2, BC2 can be prepared in the same manner shown above for BA, BB and BC starting with the appropriate known starting nicotinic acid (Eur. J. Org. Chem. 2001, 1371).

Intermediate BA1 4,6-dichloronicotinic acid

Intermediate BB1 3,3-dichloro-1-(4,6-dichloro-3-pyridinyl)-2-propen-1-one

Intermediate BC1 3,3-dianilino-1-(4,6-dichloro-3-pyridinyl)-2-propen-1-one

Intermediate BA2 4,5-dichloronicotinic acid

Intermediate BB2 3,3-dichloro-1-(4,5-dichloro-3-pyridinyl)-2-propen-1-one

Intermediate BC2 3,3-dianilino-1-(4,5-dichloro-3-pyridinyl)-2-propen-1-one

Example 39 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one

A mixture of 3,3-dianilino-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one (100 mg, 0.25 mmol) and t-BuOK (42 mg, 0.38 mmol) in anhydrous dioxane (4 mL) was heated to 80° C. for 4 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The solution was washed with water and brine, dried over MgSO₄, and concentrated in vcaco. Silica gel flash chromatography of the residue using 1:1 EtOAc:Hex gave 2-anilino-5-chloro-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (13 mg, 14%): LCMS RT: 2.47 min, MH⁺: 362 and 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (68 mg, 75%): LCMS RT: 2.24 min, MH⁺: 362.3. Alternatively, the cyclization could be achieved by using other bases such as NaH and other aprotic solvents such as THF and DMF.

Examples 40 and 41 can be prepared in the same manner as that for Example 39 above.

Example 40 2-anilino-7-chloro-1-phenyl-1,6-naphthyridin-4(1H)-one

Example 41 2-anilino-8-chloro-1-phenyl-1,6-naphthyridin-4(1H)-one

Example 42 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one

To a solution of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (80 mg, 0.22 mmol) in THF (3 mL) was added Ni(dppp)Cl₂ (24 mg, 0.044 mmol) at room temperature. After stirring for a few minutes MeMgBr (3M, 0.59 mL, 1.76 mmol) was added and the mixture was allowed to stir for 24 h. The mixture was quenched with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. Purification by reverse-phase preparative HPLC (10% CH₃CN in water with 0.1% TFA to 95% CH₃CN in water, 10 mL/min, 10 min) provided 2-anilino-5,7-dimethyl-1-phenyl-1,6-naphthyridin-4(1H)-one (31 mg, 40%): LCMS RT: 1.51 min, MH⁺: 342.4.

Example 43 2-anilino-5-(dimethylamino)-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one

A mixture of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (80 mg, 0.22 mmol) and dimethylamine (3M in THF, 0.73 mL, 2.20 mmol) in dioxane (3 mL) was heated to 80° C. for 24 h. The reaction mixture was cooled, concentrated in vacuo, diluted with water and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na₂SO₄, and concentrated in vacuo to give 2-anilino-5-(dimethylamino)-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (74 mg, 91%): LCMS RT: 1.86 min, MH⁺: 371.3

Example 44 Ethyl[(2-anilino-7-methyl-4-oxo-1-phenyl-1,4 dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetate

A solution of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (200 mg, 0.55 mmol) in EtOH (10 mL) was added ethyl 2-mercaptoacetate (0.12 mL, 1.10 mmol) and TEA (0.23 mL, 1.65 mmol). The reaction was heated at reflux for 24 h. The reaction mixture was cooled, concentrated in vacuo, diluted with water and extracted is with EtOAc. The combined organic extracts were washed with water, brine, and dried over Na₂SO₄. Solvents were removed in vacuo and the residue was purified by reverse-phase preparative HPLC (10% CH₃CN in water with 0.1% TFA to 95% CH₃CN in water, 10 mL/min, 10 min) to provide ethyl [(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetate (120 mg, 49%): LCMS RT: 3.07 min, MH⁺: 446.2.

Example 45 [(2-anilino-7-methyl-4-ox -1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetic acid

Aqueous NaOH (2N, 1 mL) was added to a stirred solution of ethyl[(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetate (100 mg, 0.23 mmol) in EtOH (8 mL) at room temperature. The mixture was allowed to stir for 4 h and was concentrated in vacuo. The reaction mixture was acidified with 1N HCl and extracted with CH₂Cl₂. The organic layer was dried over MgSO₄ and concentrated in vacuo. Purification by reverse-phase preparative HPLC (10% CH₃CN in water with 0.1% TFA to 95% CH₃CN in water, 10 mL/min, 10 min) provided [(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetic acid (56 mg, 60%): LCMS RT: 2.61 min, MH⁺: 418.2.

Example 46 Ethyl N-(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)glycinate

To a solution of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (80 mg, 0.22 mmol) in EtOH (8 mL) was added glycine ethyl ester hydrochloride (46 mg, 0.44 mmol) and TEA (0.23 mL, 1.65 mmol). The reaction was heated at reflux for 3 d. The reaction mixture was cooled, concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC (10% CH₃CN in water with 0.1% TFA to 95% CH₃CN in water, 10 mL/min, 10 min) to provide ethyl N-(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)glycinate (43 mg, 46%): LCMS RT: 2.16 min, MH⁺: 429.3.

Example 47 2-[(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]-N-cyclopropylacetamide

To a mixture of [(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetic acid (20 mg, 0.05 mmol), EDCI (18 mg, 0.10 mmol), HOBT (13 mg, 0.10 mmol) and cyclopropylamine (0.004 mL, 0.06 mmol) in CH₂Cl₂ (5 mL) was added TEA (0.02 mL, 0.14 mmol). The reaction solution was stirred at room temperature for 24 h before the mixture was diluted with CH₂Cl₂, washed with 0.5N HCl, saturated aqueous NaHCO₃, brine and dried over Na₂SO₄. Solvents were removed in vacuo and the residue was purified by reverse-phase preparative HPLC (10% CH₃CN in water with 0.1% TFA to 95% CH₃CN in water, 10 mL/min, 10 min) to provide 2-[(2-anilino-7-methyl4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]-N-cyclopropylacetamide (13 mg, 59%): LCMS RT: 2.55 min, MH⁺: 457.1.

Example 48 2-anilino-7-methyl-1-phenyl-5-(2,2,2-trifuoroethoxy)-1,6-naphthyridin-4(1H)-one

Trifluoroethanol (0.08 mL, 1.1 mmol) was added to a suspension of NaH (60% oil dispersion, 44 mg, 1.1 mmol) in DMSO (4 mL) at 0° C., and the mixture was heated at 60° C. for 1 h. The mixture was cooled to room temperature and a solution of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (200 mg, 0.55 mmol) in DMSO (2 mL) was added. The resulting mixture was stirred at 50° C. for 16 h. The reaction mixture was cooled, poured into ice water and extracted with CH₂Cl₂. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. The residue was purified by a Biotage silica gel chromatography (2:1 EtOAc:Hex) to provide 2-anilino-7-methyl-1-phenyl-5-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-4(1H)-one (159 mg, 68%): LCMS RT: 2.65 min, MH⁺: 426.4. This transformation can be accomplished by using other aprotic solvents such as DMF, THF and dioxane with temperatures appropriate for these solvents. Commercially available alkoxides can also be used in the absence of base.

Example 49 2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridine-5-carboxylic acid

2-Anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (1.0 g, 2.8 mmol), DPPP (64 mg, 0.15 mmol), Pd(OAc)₂ (31 mg, 0.14 mmol), Cs₂CO₃ (580 mg, 4.20 mmol) were dissolved in EtOH (10 mL) and DMF (10 mL). A balloon filled with CO was attached to the flask and the solution was stirred vigorously. The flask was purged with CO for 5 min before it was heated to 70° C. After 4 h the mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with water, brine, and dried over Na₂SO₄. Solvents were removed in vacuo and the residue was triturated with Et₂O to give ethyl 2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridine-5-carboxylate (800 mg, 71%). The ethyl ester was then dissolved in MEOH (5 mL), and THF (20 mL). To this stirring solution was added KOH (3N, 10 mL) and the mixture was stirred at room temperature for 6 h before it was extracted with Et₂O. The aqueous layer was acidified with 2N HCl to pH=1 and the product precipitated out of the solution. The solid was filtered and dried to give 2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridine-5-carboxylic acid as a white solid (683 mg, 92%): LCMS RT: 1.75 min, MH⁺: 372.9.

Example 50 2-anilino-N-methoxy-N,7-dimethyl-4-oxo-1-phenyl-1,4-dihydro-1,6 naphthyridine-5-carboxamide

2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridine-5-carboxylic acid (80 mg, 0.22 mmol), N,O-dimethylhydroxylamine hydrochloride (64 mg, 0.66 mmol), HOBT (89 mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol) were dissolved in CH₂Cl₂ (9 mL). To this solution was added TEA (120 uL, 0.88 mmol). The reaction was stirred for 1 h and was diluted with CH₂Cl₂, washed with 0.5N HCl, saturated NaHCO₃, and brine. The organic layer was collected, dried over Na₂SO₄, and concentrated in vacuo. The solid obtained was triturated with Et₂O and dried to give 2-anilino-N-methoxy-N,7-dimethyl-4-oxo-1-phenyl-1,4-dihydro-1,6 naphthyridine-5-carboxamide as a light yellow solid (50 mg, 55%): LCMS RT: 2.08 min, MH⁺: 414.9. This transformation can also be accomplished by coupling the appropriate amine with the corresponding acid chloride.

Example 51 5-acetyl-2-anilino-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one

2-Anilino-N-methoxy-N,7-dimethyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridine-5-carboxamide (60 mg, 0.14 mmol) was suspended in THF (5 mL). To this stirring suspension at 0° C. was added MeMgBr (0.19 mL, 0.56 mmol, 3M in Et₂O). The reaction was stirred at room temperature for 6 h and quenched with saturated aqueous NH₄Cl, diluted with EtOAc, and washed with brine. The organic layer was collected, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by Biotage silica gel chromatography using EtOAc as the eluent to provide 5-acetyl-2-anilino-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one as a light yellow solid (34 mg, 66%): LCMS RT: 2.20 min, MH⁺: 370.4.

Example 52 2-anilino-7-methyl-1-phenyl-5-(trifluoromethyl)-1,6-naphthyridin-4(1H)-one

And Example 53 7-methyl-2-[methyl(phenyl)amino]-1-phenyl-5-(trifluoromethyl)-1,6-naphthyridin-4(1H)-one

A mixture of methyl fluorosulphonyldifluoroacetate (0.78 mL, 6.10 mmol) and 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (2.0 g, 5.50 mmol) in DMF (15 mL) was mixed with Copper(I) iodide (1.05 g, 5.50 mmol) at 80° C. for 6 h before the mixture was filtered and concentrated in vacuo. The residue was diluted with CH₂Cl₂, washed with water and brine, and dried over MgSO₄. Solvents were removed in vacuo and the residue was purified by Biotage silica gel chromatography using 1:1 EtOAc:Hex to provide 2-anilino-7-methyl-1-phenyl-5-(trifluoromethyl)-1,6-naphthyridin-4(1H)-one as a light yellow solid (477 mg 220%): LCMS RT: 2.68 min, MH⁺: 396.2. 7-Methyl-2-[methyl(phenyl)amino]-1-phenyl-5-(trifluoromethyl)-1,6-naphthyridin-4(1H)-one (270 mg, 12%) was also isolated: LCMS RT: 2.32 min, MH⁺: 410.4.

Example 54 2-anilino-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one

To a flask containing 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (10 mg, 0.03 mmol) in EtOAc (2 mL) and EtOH (2 mL) at room temperature was added a drop of TEA, and Pd/C (10 weight % on activated carbon Degussa type E101, 2 mg). The system was purged with H₂ and left stirring at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo to provide 2-anilino-7-methyl-1-phenyl-1,6naphthyridin-4(1H)-one (8 mg, 91%): LCMS RT: 1.22 min, MH⁺: 328.3.

Example 55 2-anilino-5-(4-methoxyphenyl)-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one

An 8-mL amber vial was charged with 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (72 mg, 0.20 mmol), 4-methoxyphenylboronic acid (36 mg, 0.24 mmol), Pd(OAc)₂ (1 mg, 0.02 mmol), Ph₃P (5 mg, 0.02 mmol), K₂CO₃ (110 mg, 0.8 mmol, 2 M), and DME (2 mL). The mixture was heated to 90° C. 2 d. Water was added to the reaction mixture and it was extracted with CH₂Cl₂. The organic layer was dried over Na₂SO₄. The residue after concentration in vacuo was triturated with Et₂O to provide 2-anilino-5-(4-methoxyphenyl)-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (54 mg, 63%): LCMS RT: 1.92 min, MH⁺: 434.5.

Utilizing the above described procedures for intermediates and examples alone or in combination, a variety of Formula I compounds were prepared using the appropriate material and the representative procedure described. These results are summarized in Table 1A.

TABLE 1A LCMS RT Representative Example Structure (min) [M + H] Procedure 56

2.07 413.4 Intermediate Z, AA, AB and Example 16, 2 57

1.85 357.3 Intermediate Z, AA, AB and Example 16, 2 58

1.67 412.2 Intermediate Z, AA, AB and Example 16, 2 59

2.18 411.4 Intermediate Z, AA, AB and Example 16, 2 60

2.02 358.4 Intermediate Z, AA, AB and Example 16, 9 61

2.54 382.3 Intermediate F, G, H, I, J and Example 1 62

2.58 432.4 Intermediate O, P, Q, R and Example 4 63

2.63 296.3 Intermediate O, P, Q, R and Example 4 64

2.89 426.2 Intermediate F, G, H, I, J and Example 9 65

3.00 426.2 Intermediate Intermediate F, G, H, I, J and Example 4 66

3.02 410.4 Intermediate A, B, C, D, E and Example 5 67

3.00 464.2 Intermediate F, G, H, I, J and Example 4 68

2.98 500.3 Intermediate F, G, H, I, J and Example 4 69

2.57 432.3 Intermediate O, P, Q, R and Example 4 70

2.50 471.1 Intermediate F, G, H, I, J and Example 6, 7 71

2.73 390.4 Intermediate O, P, Q, R and Example 4 72

2.73 408.5 Intermediate O, P, Q, R and Example 4 73

3.30 396.4 Intermediate O, P, Q, R and Example 4 74

3.41 370.4 Intermediate O, P, Q, R and Example 5 75

3.56 396.5 Intermediate O, P, Q, R and Example 5 76

3.39 404.4 Intermediate O, P, Q, R and Example 5 77

2.69 370.3 Intermediate O, P, Q, R and Example 5 78

2.59 356.3 Intermediate O, P, Q, R and Example 5 79

2.74 408.4 Intermediate O, P, Q, R and Example 4 80

1.60 394.0 Intermediate A, B, C, D, E and Example 1, 10, 11 81

2.88 376.4 Intermediate S, T, U, W and Example 15 82

2.42 348.3 Intermediate S, T, U, W and Example 15 83

1.69 426.2 Intermediate Z, AA, AB and Example 16, 2 84

3.87 480.4 Intermediate A, B, C, D, E, AL and Example 4 85

Intermediate A, B, C, D, E, AL and Example 4 86

2.43 283.6 Intermediate S, T, V and Example 15 87

2.82 620.4 Intermediate A, B, C, D, E and Example 2, 13 88

1.86 389.1 Intermediate K, L, M, N, AM, and Example 1, 13 89

2.56 372.3 Intermediate Z, AA, AB and Example 16, 17, 7 90

2.41 504.2 Intermediate A, B, C, D, E and Example 2, 12 91

2.50 518.3 Intermediate A, B, C, D, E and Example 2, 12 92

2.71 566.3 Intermediate A, B, C, D, E and Example 2, 12 93

2.54 417.4 Intermediate K, L, M, N, and Example 2 94

2.27 342.4 Intermediate S, T, U, W and Example 15 95

1.71 426.2 Intermediate A, B, C, D, E and Example 2 96

1.74 412.1 Intermediate A, B, C, D, E and Example 2 97

2.75 411.2 Intermediate A, B, C, D, E and Example 2 98

2.70 397.2 Intermediate A, B, C, D, E and Example 2 99

2.52 399.4 Intermediate A, B, C, D, E and Example 2 100

2.80 488.6 Intermediate A, B, C, D, E and Example 2 101

2.89 459.7 Intermediate A, B, C, D, E and Example 2 102

2.54 441.6 Intermediate A, B, C, D, E and Example 2 103

2.40 383.5 Intermediate A, B, C, D, E and Example 2 104

2.44 467.5 Intermediate F, G, H, I, J and Example 8 105

2.51 480.4 Intermediate F, G, H, I, J and Example 8 106

1.80 466.4 Intermediate F, G, H, I, J and Example 8 107

2.65 433.4 Intermediate A, B, C, D, E and Example 3 108

2.60 437.4 Intermediate A, B, C, D, E and Example 3 109

2.71 453.4 Intermediate A, B, C, D, E and Example 3 110

2.53 449.4 Intermediate A, B, C, D, E and Example 3 111

2.65 433.4 Intermediate A, B, C, D, E and Example 3 112

2.84 461.5 Intermediate A, B, C, D, E and Example 3 113

2.08 387.4 Intermediate A, B, C, D, E and Example 2 114

2.46 433.4 Intermediate A, B, C, D, E and Example 2 115

2.64 451.3 Intermediate A, B, C, D, E and Example 2 116

2.61 463.4 Intermediate A, B, C, D, E and Example 2 117

2.03 440.4 Intermediate A, B, C, D, E and Example 2 118

2.58 372.2 Intermediate A, B, C, D, E and Example 9 119

2.20 454.4 Intermediate A, B, C, D, E and Example 2, 13 120

2.55 496.4 Intermediate A, B, C, D, E and Example 2, 13 121

2.52 552.2 Intermediate A, B, C, D, E and Example 2, 12 122

2.44 516.3 Intermediate A, B, C, D, E and Example 2, 13 123

2.28 429.3 Intermediate A, B, C, D, E and Example 3 124

2.45 431.4 Intermediate K, L, M, N, AH and Example 2 125

2.45 362.3 Intermediate K, L, M, N and Example 9 126

2.51 360.3 Intermediate K, L, M, N, AH and Example 1 127

2.30 346.4 Intermediate K, L, M, N, AH and Example 1 128

2.70 374.4 Intermediate K, L, M, N, AH and Example 1 129

2.69 438.3 Intermediate K, L, M, N and Example 9, 14, 4 130

2.64 428.3 Intermediate K, L, M, N and Example 9, 14, 4 131

2.74 468.3 Intermediate 2 K, L, M, N and Example 9, 14, 4 132

2.77 456.4 Intermediate K, L, M, N and Example 9, 14, 4 133

2.37 364.3 Intermediate S, T, U, W and Example 15 134

2.40 362.3 Intermediate S, T, V, X and Example 15 135

2.46 362.2 Intermediate S, T, V, X and Example 15 136

2.28 346.3 Intermediate S, T, V, X and Example 15 137

2.32 342.3 Intermediate S, T, V, X and Example 15 138

2.27 346.3 Intermediate S, T, V, X and Example 15 139

2.41 362.3 Intermediate S, T, V, X and Example 15 140

2.36 358.3 Intermediate S, T, V, X and Example 15 141

2.32 358.3 Intermediate S, T, V, X and Example 15 142

2.36 358.3 Intermediate S, T, V, X and Example 15 143

2.35 364.3 Intermediate A, B, C, D, E and Example 1 144

2.60 406.3 Intermediate Y, S, T, U, W and Example 15 145

5.35 434.4 Intermediate Y, S, T, U, W and Example 15, 4 146

3.43 470.3 Intermediate F, G, H, I, J and Example 6 147

3.43 470.3 Intermediate F, G, H, I, J and Example 6 148

2.59 541.3 Intermediate F, G, H, I, J and Example 6, 7, 13 149

2.66 525.2 Intermediate F, G, H, I, J and Example 6, 7, 13 150

2.49 483.4 Intermediate F, G, H, I, J and Example 8 151

2.38 455.3 Intermediate F, G, H, I, J and Example 8, 7 152

2.60 499.4 Intermediate F, G, H, I, J and Example 6, 7, 13 153

2.95 547.4 Intermediate F, G, H, I, J and Example 6, 7, 13 154

2.19 482.3 Intermediate F, G, H, I, J and Example 8, 7, 13 155

2.07 482.3 Intermediate F, G, H, I, J and Example 8, 7, 13 156

1.95 454.3 Intermediate F, G, H, I, J and Example 8, 7, 13 157

2.18 524.3 Intermediate F, G, H, I, J and Example 8, 7, 13 158

2.44 530.3 Intermediate F, G, H, I, J and Example 8, 7, 13 159

1.99 468.3 Intermediate F, G, H, I, J and Example 8, 7, 13 160

2.74 598.3 Intermediate F, G, H, I, J and Example 8, 7, 13 161

3.15 442.3 Intermediate F, G, H, I, J and Example 6 162

328 456.2 Intermediate F, G, H, I, J and Example 6 163

2.26 471.3 Intermediate F, G, H, I, J and Example 6, 7, 13 164

2.34 485.3 Intermediate F, G, H, I, J and Example 6, 7, 13 165

2.71 398.4 Intermediate Z, AA, AB and Example 16 166

2.88 542.6 Intermediate F, G, H, I, J and Example 8 167

2.66 495.6 Intermediate F, G, H, I, J and Example 8 168

2.20 441.5 Intermediate F, G, H, I, J and Example 8 169

2.76 453.5 Intermediate F, G, H, I, J and Example 8 170

3.05 430.3 Intermediate K, L, M, N, AI and Example 1 171

3.14 428.4 Intermediate K, L, M, N, AI and Example 1 172

2.72 477.5 Intermediate A, B, C, D, E and Example 2 173

2.72 495.5 Intermediate F, G, H, I, J and Example 8 174

2.72 495.6 Intermediate F, G, H, I, J and Example 8 175

2.77 487.5 Intermediate F, G, H, I, J and Example 8 176

2.43 437.4 Intermediate A, B, C, D, E and Example 2 177

3.13 502.5 Intermediate F, G, H, I, J and Example 6, 21 178

2.93 488.3 Intermediate F, G, H, I, J and Example 6, 21 179

2.41 426.3 Intermediate F, G, H, I, J and Example 17, 7 180

2.56 372.3 Intermediate Z, AA, AB and Example 16, 17, 7 181

2.19 408.2 Intermediate A, B, C, D, E and Example 17, 7 182

2.39 425.4 Intermediate F, G, H, I, J and Example 17, 18 183

2.18 407.4 Intermediate A, B, C, D, E and Example 17, 18 184

2.88 424.4 Intermediate F, G, H, I, J and Example 17, 7, 19, 20 185

2.27 402.2 Intermediate Z, AA, AB and Example 16, 9 186

2.41 408.3 Intermediate Z, AA, AB and Example 16, 9 187

2.50 426.3 Intermediate Z, AA, AB and Example 16, 9 188

2.43 386.1 Intermediate Z, AA, AB and Example 16, 9 189

2.66 456.4 Intermediate F, G, H, I, J and Example 9 190

2.88 462.5 Intermediate F, G, H, I, J and Example 9 191

2.98 452.4 Intermediate F, G, H, I, J and Example 9 192

3.12 480.3 Intermediate F, G, H, I, J and Example 9 193

3.10 440.1 Intermediate F, G, H, I, J and Example 9 194

2.51 398.1 Intermediate Z, AA, AB and Example 16, 9 195

2.99 505.4 Intermediate F, G, H, I, J and Example 8 196

3.05 513.5 Intermediate F, G, H, I, J and Example 8 197

2.47 455.4 Intermediate F, G, H, I, J and Example 8 198

2.57 453.4 Intermediate K, L, M, N₁ and Example 2 199

2.70 440.2 Intermediate K, L, M, N₂ and Example 17 200

2.19 411.3 Intermediate K, L, M, N₂ and Example 17, 18 201

2.48 453.4 Intermediate K, L, M, N₂ and Example 2 202

2.76 440.2 Intermediate K, L, M, N₁ and Example 17 203

2.76 481.5 Intermediate K, L, M, N₁ and Example 2 204

2.69 481.5 Intermediate K, L, M, N₂ and Example 2 205

2.23 411.3 Intermediate K, L, M, N₁ and Example 17, 18 206

2.27 383.4 Intermediate K, L, AC, AG and Example 2 207

3.12 490.3 Intermediate F, G, H, I, J and Example 17 208

2.55 461.3 Intermediate F, G, H, I, J and Example 17, 18 209

2.62 503.4 Intermediate F, G, H, I, J and Example 8 210

2.82 531.5 Intermediate F, G, H, I, J and Example 8 211

2.54 491.4 Intermediate F, G, H, I, J and Example 8 212

2.93 531.4 Intermediate F, G, H, I, J and Example 8 213

2.47 491.4 Intermediate F, G, H, I, J and Example 8 214

3.02 476.3 Intermediate F, G, H, I, J and Example 9 215

2.75 492.3 Intermediate F, G, H, I, J and Example 9 216

3.14 476.2 Intermediate F, G, H, I, J and Example 9 217

2.83 492.3 Intermediate F, G, H, I, J and Example 9 218

2.15 349.1 Intermediate K, L, M, N₃ and Example 2 219

2.01 362.3 Intermediate K, L, M, N and Example 17, 25 220

2.87 505.4 Intermediate AH, K, L, M, N₂ 221

2.90 396.3 Intermediate AH, K, L, M, N and Example 1 222

3.23 424.3 Intermediate AH, K, L, M, N and Example 1 223

2.67 396.3 Intermediate AH, K, L, M, N₂ and Example 1 224

3.02 424.4 Intermediate AH, K, L, M, N₂ and Example, 1 225

2.12 401.3 Intermediate A, B, C, D, E and Example 3, 7 226

2.45 459.4 Intermediate K, L, M, N, AI and Example 2 227

2.69 487.5 Intermediate K, L, M, N, AI and Example 2 228

2.37 447.4 Intermediate K, L, M, N, AI and Example 2 229

2.60 374.3 Intermediate K, L, M, N, AI and Example 1 230

2.78 390.1 Intermediate K, L, M, N, AM and Example 1 231

2.09 421.2 Intermediate A, B, C, D, E and Example 22 232

2.44 483.2 Intermediate A, B, C, D, E and Example 22 233

2.51 497.2 Intermediate A, B, C, D, E and Example 22 234

2.44 383.2 Intermediate A, B, C, D, E and Example 3 235

2.84 428.4 Intermediate A, B, C, D, E and Example 17 236

2.77 400.3 Intermediate A, B, C, D, E and Example 17 237

2.30 372.2 Intermediate A, B, C, D, E and Example 17, 7 238

2.50 427.4 Intermediate A, B, C, D, E and Example 17, 7, 13 239

2.18 441.5 Intermediate A, B, C, D, E and Example 17, 7, 13 240

2.44 399.4 Intermediate A, B, C, D, E and Example 17, 7, 13 241

2.66 455.5 Intermediate A, B, C, D, E and Example 17, 7, 13 242

2.79 427.3 Intermediate A, B, C, D, E and Example 17, 7, 13 243

2.58 411.3 Intermediate A, B, C, D, E and Example 17, 7, 13 244

2.58 457.3 Intermediate A, B, C, D, E and Example 17, 7, 13 245

2.80 447.5 Intermediate A, B, C, D, E and Example 17, 7, 13 246

2.97 481.8 Intermediate A, B, C, D, E and Example 17, 7, 13 247

3.30 481.3 Intermediate A, B, C, D, E and Example 17, 7, 13 248

3.05 481.7 Intermediate A, B, C, D, E and Example 17, 7, 13 249

1.99 371.4 Intermediate A, B, C, D, E and Example 17, 18 250

2.82 384.4 Intermediate A, B, C, D, E and Example 17, 7, 19, 20 251

2.94 398.4 Intermediate A, B, C, D, E and Example 17, 7, 19, 20 252

3.22 426.4 Intermediate A, B, C, D, E and Example 17, 7, 19, 20 253

3.05 412.4 Intermediate A, B, C, D, E and Example 17, 7, 19, 20 254

3.10 424.4 Intermediate A, B, C, D, E and Example 17, 7, 19, 20 255

3.19 438.4 Intermediate A, B, C, D, E and Example 17, 7, 19, 20 256

2.96 432.4 Intermediate A, B, C, D, E and Example 17, 7, 19, 20 257

3.16 466.4 Intermediate A, B, C, D, E and Example 17, 7, 19, 20 258

2.80 398.5 Intermediate A, B, C, D, E and Example 17, 7, 19, 20 259

2.95 412.5 Intermediate A, B, C, D, E and Example 17, 7, 19, 20 260

2.80 438.6 Intermediate A, B, C, D, E and Example 17, 7, 19, 20 261

3.06 450.3 Intermediate A, B, C, D, E and Example 17, 7, 19, 20 262

3.05 450.4 Intermediate A, B, C, D, E and Example 17, 7, 19, 20 263

1.94 376.2 Intermediate K, L, M, N and Example 17, 7 264

2.44 374.4 Intermediate K, L, M, N and Example 17, 7, 19, 20 265

2.59 388.3 Intermediate K, L, M, N and Example 17, 7, 19, 20 266

2.68 442.4 Intermediate K, L, M, N and Example 17, 7, 19, 20 267

2.97 470.5 Intermediate K, L, M, N and Example 17, 7, 19, 20 268

2.53 376.3 Intermediate K, L, M, N and Example 9 269

2.28 405.4 Intermediate K, L, M, N and Example 2 270

2.35 406.2 Intermediate K, L, M, N and Example 9 271

2.70 390.2 Intermediate K, L, M, N Example 9 272

2.20 417.3 Intermediate K, L, M, N, AI and Example 17, 18 273

2.38 386.3 Intermediate A, B, C, D, E and Example 17, 7, 19, 20, 25 274

2.63 440.3 Intermediate A, B, C, D, E and Example 17, 7, 19, 20, 25 275

2.83 468.3 Intermediate A, B, C, D, E and Example 17, 7, 19, 20, 25 276

2.79 479.3 Intermediate F, G, H, I, J and Example 8 277

2.58 451.2 Intermediate F, G, H, I, J and Example 8 278

2.58 356.4 Intermediate Y, S, T, U, W and Example 15, 34 279

2.79 404.4 Intermediate Y, S, T, U, W and Example 15, 4 280

2.93 422.4 Intermediate Y, S, T, U, W and Example 15, 4 281

2.78 384.4 Intermediate Y, S, T, U, W and Example 15, 34 282

2.50 442.2 (423 + H2O + 1) Intermediate Y, S, T, U, W and Example 15, 34 283

2.26 372.4 Intermediate Y, S, T, U, W and Example 15, 34 284

2.29 427.4 Intermediate Y, S, T, U, W and Example 15, 31, 32, 33, 13 285

2.19 413.4 Intermediate Y, S, T, U, W and Example 15, 31, 32, 33, 13 286

2.15 384.4 Intermediate Y, S, T, U, W and Example 15 ,31, 32 287

2.01 386.4 Intermediate Y, S, T, U, W and Example 15, 31, 32, 33 288

2.42 396.5 Intermediate Y, S, T, U, W and Example 15, 31 289

2.97 430.6 Intermediate Y, S, T, U, W and Example 15, 31 290

2.33 398.6 Intermediate Y, S, T, U, W and Example 15, 31, 33 291

2.87 432.4 Intermediate Y, S, T, U, W and Example 15, 31, 33 292

2.01 397.3 Intermediate Y, S, T, U, W and Example 15, 31, 32, 13 293

2.00 399.5 Intermediate Y, S, T, U, W and Example 15, 31, 32, 33, 13 294

2.63 461.3 Intermediate F, G, H, I, J and Example 17, 18 295

2.54 445.5 Intermediate K, L, M, N and Example 2 296

2.27 425.3 Intermediate Y, S, T, U, W and Example 15, 31, 32, 13 297

2.43 392.3 Intermediate Y, S, T, U, W and Example 15 298

2.40 398.5 Intermediate Y, S, T, U, W and Example 15, 31 299

2.28 411.4 Intermediate Y, S, T, U, W and Example 15, 31, 32, 13 300

3.18 490.0 Intermediate F, G, H, I, J and Example 9 301

2.90 462.3 Intermediate F, G, H, I, J and Example 9 302

2.90 418.3 Intermediate F, G, H, I, J and Example 1 303

2.66 418.3 Intermediate F, G, H, I, J and Example 1 304

2.70 403.6 Intermediate K, L, M, N and Example 2 305

2.52 503.6 Intermediate F, G, H, I, J and Example 8 306

3.03 502.2 Intermediate F, G, H, I, J and Example 8 307

2.68 358.0 Intermediate S, T, U, W and Example 25 308

2.40 358.4 Intermediate A, B, C, D, E and Example 9

Utilizing the above described procedures for intermediates and examples alone or in combination, a variety of Formula I compounds can be prepared using the appropriate starting material and the representative procedure described. These compounds are summarizing in Table 1B.

TABLE 1B Representative Example Structure Procedure 309

Intermediate Z, AA, AB and Example 16, 4 310

Intermediate Z, AA, AB and Example 16, 2 311

Intermediate Z, AA, AB and Example 16, 3 312

Intermediate Z, AA, AB and Example 16, 2 313

Intermediate Z, AA, AB and Example 16, 2, 7 314

Intermediate Z, AA, AB and Example 16, 2 315

Intermediate Z, AA, AB and Example 16, 2, 7, 13 316

Intermediate Z, AA, AB and Example 16, 2, 7, 13 317

Intermediate Z, AA, AB and Example 16, 6, 7 318

Intermediate Z, AA, AB and Example 16, 6 319

Intermediate Z, AA, AB and Example 16, 6, 7, 13 320

Intermediate Z, AA, AB and Example 16, 6, 7, 13 321

Intermediate Z, AA, AB, and Example 16, 9, 7 322

Intermediate Z, AA, AB, and Example 16, 9 323

Intermediate Z, AA, AB, and Example 16, 9, 7, 13 324

Intermediate Z, AA, AB, and Example 16, 9, 7, 13 325

Intermediate Z, AA, AB, and Example 16, 9 326

Intermediate Z, AA, AB, and Example 16, 9 327

Intermediate Z, AA, AB, and Example 16, 9 328

Intermediate Y, S, T, U, W and Example 15, 34 329

Intermediate Y, S, T, U, W and Example 15, 34 330

Intermediate Y, S, T, U, W and Example 15, 34 331

Intermediate Y, S, T, U, W and Example 15, 34 332

Intermediate Y, S, T, U, W and Example 15, 4 333

Intermediate Y, S, T, U, W and Example 15, 4 334

Intermediate Y, S, T, U, W and Example 15, 34 335

Intermediate Y, S, T, U, W and Example 15, 34, 13 336

Intermediate Y, S, T, U, W and Example 15, 34, 13 337

Intermediate Y, S, T, U, W and Example 15, 34, 13 338

Intermediate K, L, M, N Example 31, 32 339

Intermediate O, P, Q, R and Example 17, 25, 26 340

Intermediate F, G, H, I, J and Example 31, 32 341

Intermediate A, B, C, D, E and Example 1 and Intermediate AK 342

Intermediate Z, AA, AB and Example 16, 31, 32, 33 343

Intermediate A, B, C, D, E and Example 1 and Intermediate AK 344

Intermediate A, B, C, D, E and Example 31, 32 345

Intermediate A, B, C, D, E and Example 1 and Interemediate AK 346

Intermediate O, P, Q, R and Example 17, 25, 26 347

Intermediate Z, AA, AB, and Example 16, 31, 32 348

Intermediate F, G, H, I, J and Example 31, 32, 33 349

Intermediate O, P, Q, R and Example 17, 25, 26 350

Intermediate K, L, M, N and Example 31 351

Intermediate F, G, H, I, J and Example 31 352

Intermediate Z, AA, AB and Example 16, 31 353

Intermediate Z, AA, AB and Example 16, 31 354

Intermediate A, B, C, D, E and Example 31, 32, 33 355

Intermediate K, L, M, N and Example 31, 32, 33 356

Intermediate O, P, Q, R and Example 17, 25, 26 357

Intermediate A, B, C, D, E AJ and Example 1 358

Intermediate A, B, C, D, E and Example 1 and Intermediate AL 359

Intermediate Z, AA, AB, and Example 16, 5 360

Intermediate Z, AA, AB, and Example 16, 5 361

Intermediate A, AA, AB, and Example 16, 4 362

Intermediate K, L, M, N, and Example 2 363

Intermediate K, L, M, N, and Example 2 364

Intermediate K, L, M, N, and Example 2 365

Intermediate K, L, M, N, and Example 2 366

Intermediate K, L, M, N, and Example 2 367

Intermediate K, L, M, N, and Example 2 368

Intermediate K, L, M, N, and Example 2 369

Intermediate K, L, M, N, and Example 2 370

Intermediate K, L, M, N, and Example 2 371

Intermediate A, B, C, D, E and Example 2 372

Intermediate A, B, C, D, E and Example 2 373

Intermediate A, B, C, D, E and Example 2 374

Intermediate A, B, C, D, E and Example 2 375

Intermediate A, B, C, D, E and Example 2 376

Intermediate A, B, C, D, E and Example 2 377

Intermediate A, B, C, D, E and Example 2 378

Intermediate A, B, C, D, E and Example 2 379

Intermediate S, T, V, X and Example 15 380

Intermediate S, T, V, X and Example 15 381

Intermediate S, T, V, X and Example 15 and Intermediate AJ 382

Intermediate S, T, V, X and Example 15 and Intermediate AJ 383

Intermediate S, T, V and Example 15 384

Intermediate S, T, V and Example 15 385

Intermediate S, T, V and Example 15 386

Intermediate S, T, V, X and Example 15 387

Intermediate A, B, C, D, E and Example 2 388

Intermediate S, T, V and Example 15 389

Intermediate S, T, V and Example 15 390

Intermediate S, T, V, X and Example 15 391

Intermediate S, T, V, X and Example 15 392

Intermediate S, T, V and Example 15, 21 393

Intermediate S, T, V and Example 15, 21 394

Intermediate S, T, V and Example 15, 21 395

Intermediate A, B, C, D, E and Example 1, 12 396

Intermediate Z, AA, AB and Example 16, 17, 7, 19 397

Intermediate Z, AA, AB and Example 16, 17, 18 398

Intermediate Z, AA, AB and Example 16, 2 399

Intermediate Z, AA, AB and Example 16, 2 400

Intermediate Z, AA, AB and Example 16, 2, 13 401

Intermediate Z, AA, AB and Example 16, 2 402

Intermediate Z, AA, AB and Example 16, 2 403

Intermediate Z, AA, AB and Example 16, 9 404

Intermediate Z, B, C, D, E and Example 1, 10, 11 405

Intermediate A, B, C, D, E and Example 1, 10, 11 406

Intermediate A, B, C, D, E and Example 1, 10, 11 407

Intermediate A, B, C, D, E and Example 1, 10, 11 408

Intermediate Z, AA, AB and Example 16, 2, 7, 13 409

Intermediate Z, AA, AB and Example 16, 6, 7, 13 410

Intermediate Z, AA, AB and Example 16, 9, 7, 13 411

Intermediate Z, AA, AB and Example 16, 9, 7, 13 412

Intermediate Z, AA, AB and Example 16, 2, 7, 13 413

Intermediate Z, AA, AB and Example 16, 6, 7, 13 414

Intermediate Z, AA, AB and Example 16, 17, 7, 13 415

Intermediate A, AA, AB and Example 16, 17, 7, 13 416

Intermediate Z, AA, AB and Example 16, 17, 7, 13 417

Intermediate Z, AA, AB and Example 16, 17, 7, 13 418

Intermediate Z, AA, AB and Example 16, 17 419

Intermediate Z, AA, AB and Example 16, 6 420

Intermediate Z, AA, AB and Example 16, 6, 21 421

Intermediate Z, AA, AB and Example 16, 6 422

Intermediate Z, AA, AB and Example 16, 6 423

Intermediate Z, AA, AB and Example 16, 6, 21 424

Intermediate Z, AA, AB and Example 16, 6 425

Intermediate Z, AA, AB and Example 16, 3, 24 426

Intermediate K, L, M, N, AM and Example 1 and Intermediate AJ 427

Intermediate K, L, M, N, AM and Example 1 and Intermediate AJ 428

Intermediate K, L, M, N, AM and Example 1, 26 429

Intermediate K, L, M, N, AM and Example 1, 26 430

Intermediate K, L, M, N, AM and Example 1 and Intermediate AJ 431

Intermediate Z, AA, AB and Example 16, 31 432

Intermediate Z, AA, AB and Example 16, 31, 32, 13 433

Intermediate Z, AA, AB and Example 16, 31, 33 434

Intermediate Z, AA, AB and Example 16, 31, 32, 33, 13 435

Intermediate Z, AA, AB and Example 16, 31, 33 436

Intermediate Z, AA, AB and Example 16, 31, 32, 33, 13 437

Intermediate A, AA, AB and Example 16, 31, 32, 33, 13 438

Intermediate Z, AA, AB and Example 16, 17, 7, 19, 20 439

Intermediate Z, AA, AB and Example 16, 17, 7, 19, 20 440

Intermediate Z, AA, AB and Example 16, 17, 7, 19, 20 441

Intermediate Z, AA, AB and Example 16, 2, 13 442

Intermediate Z, AA, AB and Example 16, 2 and Intermediate AK 443

Intermediate Z, AA, AB and Example 16, 2, 12 444

Intermediate Z, AA, AB and Example 16, 2, 13 445

Intermediate Z, AA, AB and Example 16, 3, 24, 13 446

Intermediate Z, AA, AB and Example 16, 2, 13 447

Intermediate Z, AA, AB and Example 16, 22 448

Intermediate Z, AA, AB and Example 16, 22 449

Intermediate Z, AA, AB and Example 16, 3, 24 and Intermediate AK 450

Intermediate S, T, U, W and Example 25 and Intermediate Aj 451

Intermediate S, T, U, W and Example 25 and Intermediate AJ 452

Intermediate S, T, U, W and Example 25, 26 453

Intermediate S, T, U, W and Example 25, 26 454

Intermediate S, T, U, W and Example 25, 26 455

Intermediate S, T, U, W and Example 15 and Intermediate AL and Example 3 456

Intermediate S, T, U, W and Example 15 and Intermediate AL and Example 3 457

Intermediate S, T, U, W and Example 15 and Intermediate AL and Example 3 458

Intermediate Y, S, T, U, W and Example 15, 31, 32, 33, 19, 20 459

Intermediate Y, S, T, U, W and Example 15, 31, 33 460

Intermediate Y, S, T, U, W and Example 15, 31, 32, 33, 19, 20 461

Intermediate Y, S, T, U, W and Example 15, 17, 7, 19, 20 462

Intermediate Y, S, T, U, W and Example 15, 17, 7, 19, 20 463

Intermediate Y, S, T, U, W and Example 15, 17, 7, 19, 20 464

Intermediate Y, S, T, U, W and Example 15, 17, 25 465

Intermediate Y, S, T, U, W and Example 15, 17, 25 and Intermediate AJ 466

Intermediate Y, S, T, U, W and Example 15, 17, 25, 26 467

Intermediate Y, S, T, U, W and Example 15, 3 468

Intermediate Y, S, T, U, W and Example 15, 3 469

Intermediate Y, S, T, U, W and Example 15, 3 470

Intermediate Y, S, T, U, W and Example 15, 3 471

Intermediate Y, S, T, U, W and Example 15, 3 472

Intermediate Y, S, T, U, W and Example 15, 3, 13 473

Intermediate Y, S, T, U, W and Example 15, 3 and Intermediate AK 474

Intermediate Y, S, T, U, W, and Example 15, 3, 12 475

Intermediate Y, S, T, U, W and Example 15, 3 476

Intermediate Y, S, T, U, W and Example 15, 3 477

Intermediate Y, S, T, U, W and Example 15, 3 478

Intermediate Y, S, T, U, W and Example 15, 3, 24 479

Intermediate Y, S, T, U, W and Example 15, 3 480

Intermediate Y, S, T, U, W and Example 15, 3 481

Intermediate Y, S, T, U, W and Example 15, 3 482

Intermediate Y, S, T, U, W and Example 15, 3 483

Intermediate Y, S, T, U, W and Example 15, 3 484

Intermediate Y, S, T, U, W and Example 15, 3 485

Intermediate Y, S, T, U, W and Example 15, 3, 7 486

Intermediate Y, S, T, U, W and Example 15, 3, 18 487

Intermediate Y, S, T, U, W and Example 15, 3, 7, 13 488

Intermediate Y, S, T, U, W and Example 15, 3, 7, 13 489

Intermediate Y, S, T, U, W and Example 15, 3, 7, 13 490

Intermediate Y, S, T, U, W and Example 15, 3, 13 491

Intermediate Y, S, T, U, W and Example 15, 3, 12 492

Intermediate Y, S, T, U, W and Example 15, 3, 24 and Intermediate AK 493

Intermediate Y, S, T, U, W and Example 15, 34 494

Intermediate Y, S, T, U, W and Example 15, 34 495

Intermediate Y, S, T, U, W and Example 15, 34, 21 496

Intermediate Y, S, T, U, W and Example 15, 34, 21 497

Intermediate Y, S, T, U, W and Example 15, 34 498

Intermediate S, T, U, W and Example 15 499

Intermediate Y, S, T, U, W and Example 15, 31, 32, 33, 13 500

Intermediate Y, S, T, U, W and Example 15, 31, 32, 33, 13 501

Intermediate Y, S, T, U, W and Example 15, 31, 32, 33, 13 502

Intermediate F, G, H, I, J and Example 17, 25 and Intermediate AJ 503

Intermediate F, G, H, I, J and Example 17, 25 and Intermediate AJ 504

Intermediate F, G, H, I, J and Example 17, 25 and Intermediate AJ 505

Intermediate F, G, H, I, J and Example 8 506

Intermediate F, G, H, I, J and Example 8 507

Intermediate F, G, H, I, J and Example 8 508

Intermediate F, G, H, I, J and Example 9 509

Intermediate F, G, H, I, J and Example 9 510

Intermediate F, G, H, I, J and Example 9 511

Intermediate F, G, H, I, J and Example 9 512

Intermediate F, G, H, I, J and Example 6, 21 513

Intermediate F, G, H, I, J and Example 6 514

Intermediate F, G, H, I, J and Example 6 515

Intermediate F, G, H, I, J and Example 9 516

Intermediate F, G, H, I, J and Example 8 and Intermediate AK 517

Intermediate F, G, H, I, J and Example 31, 33 518

Intermediate F, G, H, I, J and Example 31, 33 519

Intermediate F, G, H, I, J and Example 31, 33 520

Intermediate F, G, H, I, J and Example 31, 32, 33, 13 521

Intermediate F, G, H, I, J and Example 31, 32, 33, 13 522

Intermediate F, G, H, I, J and Example 31, 32, 33, 13 523

Intermediate F, G, H, I, J and Example 31, 32, 33, 13 524

Intermediate F, G, H, I, J and Example 31, 33 525

Intermediate F, G, H, I, J and Example 3, 24, 13 526

Intermediate F, G, H, I, J and Example 3, 24, 13 527

Intermediate F, G, H, I, J and Example 3, 24 and Intermediate AK 528

Intermediate F, G, H, I, J and Example 3, 24 and Intermediate AK 529

Intermediate F, G, H, I, J and Example 9, 7 530

Intermediate F, G, H, I, J and Example 9 531

Intermediate F, G, H, I, J and Example 9, 7, 13 532

Intermediate F, G, H, I, J and Example 9, 7, 13 533

Intermediate F, G, H, I, J and Example 9, 7, 13

Utilizing the above described procedures for intermediates and examples and Flow Diagrams I-XIV alone or in combination, a variety of Formula I compounds can be prepared using the appropriate starting material. These compounds are summarized in Table 1C.

TABLE 1C Example Structure 534

535

536

537

538

539

540

541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

Utilizing the above described procedures for intermediates and examples alone or in combination, a variety of Formula II compounds were prepared using the appropriate starting material and the representative procedure described. These results are summarized in Table 2A.

TABLE 2A LCMS RT Representative Example Structure (min) [M + H] Procedure 582

2.39 372.3 Intermediate BA, BB, BC and Example 39, 48 583

2.05 401.2 Intermediate BA, BB, BC and Example 39, 46, 45 584

1.93 401.3 Intermediate BA, BB, BC and Example 39, 43 585

2.04 418.3 Intermediate BA, BB, BC and Example 39, 42 586

2.25 358.4 Intermediate BA, BB, BC and Example 39, 48 587

2.89 412.1 Intermediate BA, BB, BC and Example 39, 48 588

1.89 415.3 Intermediate BA, BB, BC and Example 39, 48 589

2.57 398.3 Intermediate BA, BB, BC and Example 39, 48 590

1.92 457.2 Intermediate BA, BB, BC and Example 39, 48 591

2.41 408.4 Intermediate BA, BB, BC and Example 39, 48 592

2.52 386.1 Intermediate BA, BB, BC and Example 39, 48 593

2.46 402.2 Intermediate BA, BB, BC and Example 39, 48 594

2.12 441.1 Intermediate BA, BB, BC and Example 39, 48 595

1.79 371.9 Intermediate BA, BB, BC and Example 39, 49, 47 596

2.36 398.3 Intermediate BA, BB, BC and Example 39 597

2.57 390.4 Intermediate BA, BB, BC and Example 39 598

3.28 400.2 Intermediate BA, BB, BC and Example 39, 48 599

2.56 422.0 Intermediate BA, BB, BC and Example 39, 48 600

2.74 414.1 Intermediate BA, BB, BC and Example 39, 48 601

2.43 398.4 Intermediate BA, BB, BC and Example 39 602

2.57 422.1 Intermediate BA, BB, BC and Example 39, 48 603

2.45 408.2 Intermediate BA, BB, BC and Example 39, 48 604

2.02 396.3 Intermediate BA, BB, BC and Example 39, 42 605

2.15 410.3 Intermediate BA, BB, BC and Example 39, 42 606

1.96 383.3 Intermediate BA, BB, BC and Example 39, 43 607

2.20 484.3 Intermediate BA, BB, BC and Example 39, 43 608

2.19 411.3 Intermediate BA, BB, BC and Example 39, 43 609

2.33 419.4 Intermediate BA, BB, BC and Example 39, 43 610

1.86 454.3 Intermediate BA, BB, BC and Example 39, 43 611

1.22 483.2 Intermediate BA, BB, BC and Example 39, 43 612

2.11 411.4 Intermediate BA, BB, BC and Example 39, 43 613

1.55 426.0 Intermediate BA, BB, BC and Example 39, 43 614

1.98 413.0 Intermediate BA, BB, BC and Example 39, 43 615

1.88 370.3 Intermediate BA, BB, BC and Example 39, 42 616

1.73 356.3 Intermediate BA, BB, BC and Example 39, 42 617

2.53 488.3 Intermediate BA, BB, BC and Example 39, 43 618

2.30 427.3 Intermediate BA, BB, BC and Example 39, 43 619

1.68 405.4 Intermediate BA, BB, BC and Example 39, 55 620

2.25 449.2 Intermediate BA, BB, BC and Example 39, 55 621

2.00 418.5 Intermediate BA, BB, BC and Example 39, 55 622

2.19 438.3 Intermediate BA, BB, BC and Example 39, 55

Utilizing the above described procedures for intermediates and examples alone or in combination, a variety of Formula II compounds can be prepared using the appropriate starting material and the representative procedure described. These compounds are summarized in Table 2B.

TABLE 2B Representative Example Stucture Procedure 623

Intermediate BA1, BB1, BC1 and Example 40, 49, 47 624

Intermediate BA1, BB1, BC1 and Example 40, 31, 32 625

Intermediate BA1, BB1, BC1 and Example 40, 43 626

Intermediate BA1, BB1, BC1 and Example 40, 43 and Intermediate AK 627

Intermediate BA1, BB1, BC1 and Example 40, 43 and Intermediate AK 628

Intermediate BA1, BB1, BC1 and Example 40, 17, 25 and Intermediate AJ 629

Intermediate BA1, BB1, BC1 and Example 40, 31, 33 630

Intermediate BA1, BB1, BC1 and Example 40, 31, 33 631

Intermediate BA1, BB1, BC1 and Example 40, 31, 32, 33, 47 632

Intermediate BA1, BB1, BC1 and Example 40, 31, 32, 33, 47 633

Intermediate BA1, BB1, BC1 and Example 40, 31, 32, 33, 47 634

Intermediate BA1, BB1, BC1 and Example 40, 31, 32, 33, 47 635

Intermediate BA1, BB1, BC1 and Example 40, 31, 33 636

Intermediate BA1, BB1, BC1 and Example 40, 17, 25 and Intermediate AJ 637

Intermediate BA1, BB1, BC1 and Example 40, 17, 25 and Intermediate AJ 638

Intermediate BA1, BB1, BC1 and Example 40, 48 639

Intermediate BA1, BB1, BC1 and Example 40, 48 640

Intermediate BA1, BB1, BC1 and Example 40, 48 641

Intermediate BA1, BB1, BC1 and Example 40, 48 642

Intermediate BA1, BB1, BC1 and Example 40, 44, 21 643

Intermediate BA1, BB1, BC1 and Example 40, 44 644

Intermediate BA1, BB1, BC1 and Example 40, 44 645

Intermediate BA1, BB1, BC1 and Example 40, 43 646

Intermediate BA1, BB1, BC1 and Example 40, 49, 47 647

Intermediate BA1, BB1, BC1 and Example 40, 43 648

Intermediate BA, BB, BC and Example 39, 17, 25, 26 649

Intermediate BA, BB, BC and Example 39, 31, 32, 33 650

Intermediate BA1, BB1, BC1 and Example 40, 43 651

Intermediate BA1, BB1, BC1 and Example 40, 43 652

Intermediate BA2, BB2, BC2 and Example 40, 31, 32 653

Intermediate BA1, BB1, BC1 and Example 40, 43 654

Intermediate BA1, BB1, BC1 and Example 40, 49, 47 655

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51 656

Intermediate BA1, BB1, BC1 and Example 40, 44 657

Intermediate BA1, BB1, BC1 and Example 40, 43 658

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51 659

Intermediate BA1, BB1, BC1 and Example 40, 43 660

Intermediate BA1, BB1, BC1 and Example 40, 44 661

Intermediate BA1, BB1, BC1 and Example 40, 49, 47 662

Intermediate BA1, BB1, BC1 and Example 40, 44, 21 663

Intermediate BA, BB, BC and Example 39, 31 664

Intermediate BA1, BB1, BC1 and Example 40, 43 665

Intermediate BA, BB, BC and Example 39, 17, 25, 26 666

Intermediate BA1, BB1, BC1 and Example 40, 44, 21 667

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51 668

Intermediate BA1, BB1, BC1 and Example 40, 43, 12 669

Intermediate BA1, BB1, BC1 and Example 40, 3 670

Intermediate BA, BB, BC and Example 39, 3 671

Intermediate BA1, BB1, BC1 and Example 40, 55 672

Intermediate BA1, BB1, BC1 and Example 40, 44, 21 673

Intermediate BA1, BB1, BC1 and Example 40, 43, 12 674

Intermediate BA1, BB1, BC1 and Example 40, 31 675

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51 676

Intermediate BA, BB, BC and Example 39, 17, 25, 26 677

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL 678

Intermediate BA1, BB1, BC1 and Example 40, 3 679

Intermediate BA1, BB1, BC1 and Example 40, 43, 12 680

Intermediate BA1, BB1, BC1 and Example 40, 48 681

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51 682

Intermediate BA, BB, BC and Example 39, 43, 12 683

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AJ 684

Intermediate BA1, BB1, BC1 and Example 40, 3 685

Intermediate BA, BB, BC and Example 39, 3, 24 686

Intermediate BA1, BB1, BC1 and Example 40, 17 687

Intermediate BA1, BB1, BC1 and Example 40, 49, 47 688

Intermediate BA2, BB2, BC2 and Example 40, 31, 32, 33 689

Intermediate BA1, BB1, BC1 and Example 40, 22 690

Intermediate BA1, BB1, BC1 and Example 40, 3 691

Intermediate BA2, BB2, BC2 and Example 4l, 55 692

Intermediate BA1, BB1, BC1 and Example 40, 44, 21 693

Intermediate BA1, BB1, BC1 and Example 40, 17, 25, 26 694

Intermediate BA1, BB1, BC1 and Example 40, 17, 25, 23 695

Intermediate BA1, BB1, BC1 and Example 40, 17, 18 696

Intermediate BA1, BB1, BC1 and Example 40, 3 24 697

Intermediate BA, BB, BC and Example 39, 17, 25 698

Intermediate BA, BB, BC and Example 39, 17, 25, 26 699

Intermediate BA2, BB2, BC2 and Example 4l, 55 700

Intermediate BA1, BB1, BC1 and Example 40, 49, 50 701

Intermediate BA, BB, BC and Example 39 54, and Intermediate AK 702

Intermediate BA1, BB1, BC1 and Example 40, 3 703

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51 704

Intermediate BA2, BB2, BC2 and Example 41, 34 705

Intermediate BA2, BB2, BC2 and Example 41, 3 706

Intermediate BA1, BB1, BC1 and Example 40, 17, 25, 26 707

Intermediate BA1, BB1, BC1 and Example 40, 44 708

Intermediate BA1, BB1, BC1 and Example 40, 43, 47 709

Intermediate BA, BB, BC and Example 39, 17, 25, 26 710

Intermediate BA1, BB1, BC1 and Example 40, 48 711

Intermediate BA2, BB2, BC2 and Example 41, 31 712

Intermediate BA1, BB1, BC1 and Example 40, 3 713

Intermediate BA, BB, BC and Example 39 54 and Intermediate AK 714

Intermediate BA2, BB2, BC2 and Example 41, 34 715

Intermediate BA1, BB1, BC1 and Example 40, 3 716

Intermediate BA1, BB1, BC1 and Example 40, 17, 25, 26 717

Intermediate BA1, BB1, BC1 and Example 40, 48 718

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51 719

Intermediate BA2, BB2, BC2 and Example 41, 3 720

Intermediate BA2, BB2, BC2 and Example 41, 34 721

Intermediate BA1, BB1, BC1 and Example 40, 55 722

Intermediate BA1, BB1, BC1 and Example 40, 44, 45 723

Intermediate BA1, BB1, BC1 and Example 40, 3 724

Intermediate BA1, BB1, BC1 and Example 40, 43, 47 725

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AK 726

Intermediate BA1, BB1, BC1 and Example 40, 17, 25, 26 727

Intermediate BA1, BB1, BC1 and Example 40, 3 728

Intermediate BA2, BB2, BC2 and Example 41, 34 729

Intermediate BA2, BB2, BC2 and Example 41, 3 730

Intermediate BA1, BB1, BC1 and Example 40, 55 731

Intermediate BA1, BB1, BC1 and Example 40, 3 732

Intermediate BA1, BB1, BC1 and Example 40, 48 733

Intermediate BA1, BB1, BC1 and Example 40, 3 734

Intermediate BA, BB, BC and Example 39, 31, 32 735

Intermediate BA1, BB1, BC1 and Example 40, 3 736

Intermediate BA1, BB1, BC1 and Example 40, 3 737

Intermediate BA1, BB1, BC1 and Example 40, 31, 32, 33 738

Intermediate BA1, BB1, BC1 and Example 40, 3 739

Intermediate BA, BB, BC and Example 39, 49, 50, 51, 25 740

Intermediate BA, BB, BC and Example 39, 17, 25, 11 741

Intermediate BA, BB, BC and Example 39, 17, 25, 11 742

Intermediate BA1, BB1, BC1 and Example 40, 42 743

Intermediate BA1, BB1, BC1 and Example 40, 42 744

Intermediate BA1, BB1, BC1 and Example 40, 42 745

Intermediate BA1, BB1, BC1 and Example 40, 42 746

Intermediate BA1, BB1, BC1 and Example 40, 17, 25 747

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51, 25 748

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51, 25 749

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51, 25 750

Intermediate BA1, BB1, BC1 and Example 40, 17, 25, 26 751

Intermediate BA1, BB1, BC1 and Example 40, 55 752

Intermediate BA1, BB1, BC1 and Example 40, 55 753

Intermediate BA1, BB1, BC1 and Example 40, 55 754

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51 755

Intermediate BA1, BB1, BC1 and Example 40, 49, 50, 51 756

Intermediate BA1, BB1, BC1 and Example 40, 49 757

Intermediate BA1, BB1, BC1 and Example 40, 43 758

Intermediate BA1, BB1, BC1 and Example 40, 43 759

Intermediate BA1, BB1, BC1 and Example 40, 43 760

Intermediate BA1, BB1, BC1 and Example 40, 43 761

Intermediate BA1, BB1, BC1 and Example 40, 43 762

Intermediate BA1, BB1, BC1 and Example 40, 43 763

Intermediate BA1, BB1, BC1 and Example 40, 43, 47 764

Intermediate BA1, BB1, BC1 and Example 40, 43, 12 765

Intermediate BA1, BB1, BC1 and Example 40, 43, 12 766

Intermediate BA1, BB1, BC1 and Example 40, 43 767

Intermediate BA1, BB1, BC1 and Example 40, 43 768

Intermediate BA1, BB1, BC1 and Example 40, 3 769

Intermediate BA1, BB1, BC1 and Example 40, 43 770

Intermediate BA1, BB1, BC1 and Example 40, 22 771

Intermediate BA1, BB1, BC1 and Example 40, 46, 45 772

Intermediate BA1, BB1, BC1 and Example 40, 46 773

Intermediate BA1, BB1, BC1 and Example 40, 46, 45, 47 774

Intermediate BA1, BB1, BC1 and Example 40, 46, 45, 47 775

Intermediate BA1, BB1, BC1 and Example 40, 46, 45, 47 776

Intermediate BA1, BB1, BC1 and Example 40, 44, 45, 47 777

Intermediate BA1, BB1, BC1 and Example 40, 44, 45, 47 778

Intermediate BA1, BB1, BC1 and Example 40, 44, 45, 47 779

Intermediate BA1, BB1, BC1 and Example 40, 48, 45 780

Intermediate BA1, BB1, BC1 and Example 40, 48 781

Intermediate BA1, BB1, BC1 and Example 40, 48, 45, 47 782

Intermediate BA1, BB1, BC1 and Example 40, 48, 45, 47 783

Intermediate BA1, BB1, BC1 and Example 40, 44 784

Intermediate BA1, BB1, BC1 and Example 40, 44, 21 785

Intermediate BA1, BB1, BC1 and Example 40, 48 786

Intermediate BA1, BB1, BC1 and Example 40, 48 787

Intermediate BA1, BB1, BC1 and Example 40, 48 788

Intermediate BA1, BB1, BC1 and Example 40, 48 789

Intermediate BA1, BB1, BC1 and Example 40, 48 790

Intermediate BA, BB, BC and Example 39, 48 791

Intermediate BA, BB, BC and Example 39, 48 792

Intermediate BA, BB, BC and Example 39, 48 793

Intermediate BA, BB, BC and Example 39, 48 794

Intermediate BA, BB, BC and Example 39, 48 795

Intermediate BA, BB, BC and Example 39, 48 796

Intermediate BA, BB, BC and Example 39, 48 797

Intermediate BA, BB, BC and Example 39, 48 798

Intermediate BA, BB, BC and Example 39, 48 799

Intermediate BA, BB, BC and Example 39, 48 800

Intermediate BA, BB, BC and Example 39, 48 801

Intermediate BA, BB, BC and Example 39, 48 802

Intermediate BA, BB, BC and Example 39, 48 803

Intermediate BA, BB, BC and Example 39, 48 804

Intermediate BA, BB, BC and Example 39, 48 805

Intermediate BA, BB, BC and Example 39, 48 806

Intermediate BA, BB, BC and Example 39, 48 807

Intermediate BA, BB, BC and Example 39, 48 808

Intermediate BA, BB, BC and Example 39, 48 809

Intermediate BA, BB, BC and Example 39, 48 810

Intermediate BA, BB, BC and Example 39, 48 811

Intermediate BA, BB, BC and Example 39, 54, 47 812

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AJ 813

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AK 814

Intermediate BA, BB, BC and Example 39, 54, 12 815

Intermediate BA, BB, BC and Example 39, 54, 12 816

Intermediate BA, BB, BC and Example 39, 54, 12 817

Intermediate BA, BB, BC and Example 39, 54, 12 818

Intermediate BA, BB, BC and Example 39, 54, 12 819

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 42 820

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL 821

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 17, 25 822

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and example 55 823

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 55 824

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 17, 25 and Intermediate AJ 825

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 17, 25 and Intermediate AJ 826

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 17, 25, 26 827

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 17, 25, 26 828

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 3 829

Intermediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 3 830

Intennediate BA, BB, BC and Example 39, 54 and Intermediate AL and Example 3 831

Intermediate BA, BB, BC and Example 39, 43 832

Intermediate BA, BB, BC and Example 39, 43 833

Intermediate BA, BB, BC and Example 39, 46, 45, 47 834

Intermediate BA, BB, BC and Example 39, 46, 45, 47 835

Intermediate BA, BB, BC and Example 39, 44, 45, 47 836

Intermediate BA, BB, BC and Example 39, 44, 45, 47 837

Intermediate BA, BB, BC and Example 39, 48, 45, 47 838

Intermediate BA, BB, BC and Example 39, 48, 45, 47 839

Intermediate BA, BB, BC and Example 39, 49, 47 840

Intermediate BA, BB, BC and Example 39, 49, 47 841

Intermediate BA, BB, BC and Example 39, 49, 47 842

Intermediate BA, BB, BC and Example 39, 49, 47 843

Intermediate BA, BB, BC and Example 39, 17 844

Intermediate BA, BB, BC and Example 39, 44 845

Intermediate BA, BB, BC and Example 39, 44 846

Intermediate BA, BB, BC and Example 39, 44 847

Intermediate BA, BB, BC and Example 39, 44 848

Intermediate BA, BB, BC and Example 39, 44, 21 849

Intermediate BA, BB, BC and Example 39, 44, 21 850

Intermediate BA, BB, BC and Example 39,48 851

Intermediate BA, BB, BC and Example 39,48 852

Intermediate BA, BB, BC and Example 39, 49, 50, 51, 25 and Intermediate AJ 853

Intermediate BA, BB, BC and Example 39, 49, 50, 51, 25 and Intermediate AJ 854

Intermediate BA, BB, BC and Example 39, 49, 50, 51, 25, 26 855

Intermediate BA, BB, BC and Example 39, 49, 50, 51, 25, 26 856

Intermediate BA, BB, BC and Example 39, 31, 33 857

Intermediate BA, BB, BC and Example 39, 31, 33 858

Intermediate BA, BB, BC and Example 39, 31, 32, 33, 47 859

Intermediate BA, BB, BC and Example 39, 31, 32, 33, 47 860

Intermediate BA, BB, BC and Example 39, 31, 33 861

Intermediate BA, BB, BC and Example 39, 31, 32, 33, 47 862

Intermediate BA, BB, BC and Example 39, 31, 32, 33, 47 863

Intermediate BA, BB, BC and Example 39, 49, 50, 51 864

Intermediate BA, BB, BC and Example 39, 49, 50, 51 865

Intermediate BA, BB, BC and Example 39, 49, 50, 51 866

Intermediate BA, BB, BC and Example 39, 43, 47 867

Intermediate BA, BB, BC and Example 39, 43 and Intermediate AK 868

Intermediate BA, BB, BC and Example 39, 3 869

Intermediate BA, BB, BC and Example 39, 43, 47 870

Intermediate BA, BB, BC and Example 39, 43, 47 871

Intermediate BA, BB, BC and Example 39, 22 872

Intermediate BA, BB, BC and Example 39, 3, 24, 12 873

Intermediate BA, BB, BC and Example 39, 3, 24 and Intermediate AK 874

Intermediate BA2, BB2, BC2 and Example 41, 34 875

Intermediate BA2, BB2, BC2 and Example 4l, 34 876

Intermediate BA2, BB2, BC2 and Example 41, 34 877

Intermediate BA2, BB2, BC2 and Example 41, 34 878

Intermediate BA2, BB2, BC2 and Example 41, 34 879

Intermediate BA2, BB2, BC2 and Example 41, 34 880

Intermediate BA2, BB2, BC2 and Example 41, 34 881

Intermediate BA2, BB2, BC2 and Example 41, 31, 32, 33, 47 882

Intermediate BA2, BB2, BC2 and Example 41, 31, 32, 33, 47 883

Intermediate BA2, BB2, BC2 and Example 41, 31, 32, 33, 47 884

Intermediate BA2, BB2, BC2 and Example 41, 31, 32, 33, 47 885

Intermediate BA2, BB2, BC2 and Example 41, 31, 32, 33, 47 886

Intermediate BA2, BB2, BC2 and Example 41, 31, 33 887

Intermediate BA2, BB2, BC2 and Example 41, 55 888

Intermediate BA2, BB2, BC2 and Example 41, 55 889

Intermediate BA2, BB2, BC2 and Example 41, 55 890

Intermediate BA2, BB2, BC2 and Example 41, 49 891

Intermediate BA2, BB2, BC2 and Example 41, 34 892

Intermediate BA2, BB2, BC2 and Example 41, 17 893

Intermediate BA2, BB2, BC2 and Example 41, 49, 47 894

Intermediate BA2, BB2, BC2 and Example 41, 49, 47 895

Intermediate BA2, BB2, BC2 and Example 41, 49, 47 896

Intermediate BA2, BB2, BC2 and Example 41, 49, 47 897

Intermediate BA2, BB2, BC2 and Example 41, 49, 47 898

Intermediate BA2, BB2, BC2 and Example 41, 34 899

Intermediate BA2, BB2, BC2 and Example 41, 34 900

Intermediate BA2, BB2, BC2 and Example 41, 34, 21 901

Intermediate BA2, BB2, BC2 and Example 41, 34, 21 902

Intermediate BA2, BB2, BC2 and Example 41, 31, 32, 33, 50, 51 903

Intermediate BA2, BB2, BC2 and Example 41, 31, 33 904

Intermediate BA2, BB2, BC2 and Example 41, 31, 32, 33, 50, 51 905

Intermediate BA2, BB2, BC2 and Example 41, 49, 50, 51 906

Intermediate BA2, BB2, BC2 and Example 41, 49, 50, 51 907

Intermediate BA2, BB2, BC2 and Example 41, 49, 50, 51 908

Intermediate BA2, BB2, BC2 and Example 41, 31, 33, 25 909

Intermediate BA2, BB2, BC2 and Example 41, 31, 33, 25 and Intermediate AJ 910

Intermediate BA2, BB2, BC2 and Example 41, 17, 25, 26 911

Intermediate BA2, BB2, BC2 and Example 41, 17, 25 912

Intermediate BA2, BB2, BC2 and Example 41, 17, 25 and Intermediate AJ 913

Intermediate BA2, BB2, BC2 and Example 41, 3 914

Intermediate BA2, BB2, BC2 and Example 41, 3 915

Intermediate BA2, BB2, BC2 and Example 41, 3 916

Intermediate BA2, BB2, BC2 and Example 41, 3 917

Intermediate BA2, BB2, BC2 and Example 41, 3 918

Intermediate BA2, BB2, BC2 and Example 41, 3 919

Intermediate BA2, BB2, BC2 and Example 41, 3 and Intermediate AK 920

Intermediate BA2, BB2, BC2 and Example 41, 3 12 921

Intermediate BA2, BB2, BC2 and Example 41, 3 922

Intermediate BA2, BB2, BC2 and Example 41, 3 923

Intermediate BA2, BB2, BC2 and Example 41, 3 924

Intermediate BA2, BB2, BC2 and Example 41, 3 24 925

Intermediate BA2, BB2, BC2 and Example 41, 3 926

Intermediate BA2, BB2, BC2 and Example 41, 3 927

Intermediate BA2, BB2, BC2 and Example 41, 3 928

Intermediate BA2, BB2, BC2 and Example 41, 3 929

Intermediate BA2, BB2, BC2 and Example 41, 3 45 930

Intermediate BA2, BB2, BC2 and Example 41, 3 18 931

Intermediate BA2, BB2, BC2 and Example 41, 3 45, 47 932

Intermediate BA2, BB2, BC2 and Example 41, 3 45, 47 933

Intermediate BA2, BB2, BC2 and Example 41, 3 24, 27 934

Intermediate BA2, BB2, BC2 and Example 41, 3 47 935

Intermediate BA2, BB2, BC2 and Example 41, 3 12 936

Intermediate BA2, BB2, BC2 and Example 41, 3 24 and Intermediate AK

Utilizing the above described procedures for intermediates and examples, and Flow Diagrams I-XIV alone or in combination, a variety of Formula II compounds can be prepared using the appropriate starting material. These compounds are summarized in Table 2C

TABLE 2C Ex- ample Structure 937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962

963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990

991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

Biological Evaluation

Demonstration of the activity of the compounds of this invention is accomplished through in vitro, ex vivo and in vivo assays that are well known in the art.

in vivo Test Procedure:

Male Wistar rats (270-330 g) were fasted overnight and then given either vehicle or compound by oral gavage. Two or three hours later, the rats were given an intraperitoneal dose of glucose (2 g/kg). The rats were tail-bled for glucose using a Glucometer (Bayer Corporation, Mishawaka, Ind.) just prior to the glucose dose and 15, 30 and 60 minutes afterward. The area under the glucose curve was calculated by the trapezoidal method for both the vehicle and treated animals, and the percent reduction in the glucose AUC by the compound calculated. A typical positive effect of the compound results in a 12-20% reduction in the AUC relative to the AUC of the vehicle-treated group. Compounds of present invention were found to have a blood glucose lowering effect in this in vivo assay.

The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing examples are included by way of illustration only. Accordingly, the scope of the invention is limited only by the scope of the appended claims. 

1. A method for treating diabetes, comprising orally administering to a mammal an effective amount of a compound of the formula (II)

wherein R^(1′) is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R⁹, or R^(1′) is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂ and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R¹⁰; R¹⁰ is selected from nitro, nitrile, hydroxy, halogen, acyl of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂ and O, NR¹¹R¹², C(═O)OR¹¹, C(═O)NHR¹¹, NHC(═O)R¹³, NHS(═O)₂R¹³, S(═O)O₀₋₂R¹³, S(═O)₂NHR¹¹, cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O); R¹³ is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms; R¹¹ and R¹² are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms; A is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and haloalkyl of 1-8 carbon atoms; R⁹ is selected from hydroxy, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, O-A-R¹⁴, NR¹¹R¹²; or R⁹ is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂ and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, all of which may be substituted with 1-3 of R¹⁰, or R⁹ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R¹⁰; R¹⁴ is selected from cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, all of which may be substituted with 1-3 of R¹⁰; with the proviso for R^(1′) that when A is CH₂, R⁹ is not optionally substituted biphenyl; R^(2′) is selected from NR¹⁵R¹⁶, S(O)₀₋₂R¹⁷, and OR¹⁷; R¹⁵ is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, A-R⁹, C(═O)R¹⁸, C(═O)NHR¹⁸, S(═O)₂NHR¹⁸; R¹⁸ is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂ and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, all of which may be substituted with 1-3 of R¹⁰, or R¹⁸ is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, and alkynyl of 2-6 carbon atoms, all of which may be substituted with 1-3 of halogen or alkoxy of 1-6 carbon atoms, or R¹⁸ is A-R⁹; R¹⁶ is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and A-R⁹, or R¹⁶ is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂ and O, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, all of which may be substituted with 1-3 of R¹⁰, or R¹⁵ and R¹⁶ combine, together with the nitrogen atom to which they are attached, to form a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂ and O, or a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R¹⁰; R¹⁷ is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, and alkynyl of 2-8 carbon atoms, haloalkyl of 1-8 carbon atoms, A-R⁹, or R¹⁷ is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂ and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, all of which may be substituted with 1-3 of R¹⁰; R^(3′) is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂ and O, cylcoalkyl of 3-8 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)₀₋₂, and O, cycloalkenyl of 4-8 carbon atoms, and heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)₀₋₂ and O, all of which may be substituted with 1-3 of R¹⁰, or R^(3′) is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR¹9R²⁰, A-OR¹⁹, A-NR¹⁹R²⁰, and A-R²⁰; R¹⁹ and R²⁰ are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R⁹, or R¹⁹ and R²⁰ are independently selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(O)₀₋₂ and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)₀₋₂ and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)₀₋₂ and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R¹⁰; R^(4′) is selected from ═O, ═S, and OR²¹; R²¹ is hydrogen, or R²¹ is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, all of which may be substituted with 1-3 of R¹⁰; cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, all of which may be substituted with 1-3 of R¹⁰, or R^(5′), R7′, and R^(8′) are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂ and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R¹⁰, A-R²³, A-NR²⁴R²⁵, C(═O)R²⁴, C(═O)OR²⁴, C(═O)NR²⁴R²⁵, S(═O)₂R²⁶, A-C(═O)R²⁴, A-C(═O)OR²⁴, or A-C(═O)NR²⁴R²⁵, or R^(5′), R^(7′), and R^(8′) are independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, haloalkyl of 1-8 carbon atoms, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, cycloalkoxy of 3-8 carbon atoms, A-R²³, A(OR²²)—R²³, NR²⁷R²⁸, A-NR²⁷R²⁸, A-Q-R²⁹, Q-R²⁹, Q-A-NR²⁴R²⁵, C(═O)R²⁴, C(═O)OR²⁴, C(═O)NR²⁴R²⁵, A-C(═O)R²⁴ , A-C(═O)OR²⁴, and A-C(═O)NR²⁴R²⁵; Q is selected from O and S(═O)₀₋₂; R²² is selected from hydrogen, alkyl of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms, and cycloalkyl of 3-8 carbon atoms; R²³ is selected from hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, and cycloalkoxy of 3-8 carbon atoms, or R²³ is selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂, and O, all of which may be substituted with 1-3 of R¹⁰, or R²³ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R¹⁰; with the proviso for A(OR²²)—R²³ that when R²³ is selected from hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, and cycloalkoxy of 3-8 carbon atoms, A is not CH; R²⁴ and R²⁵ are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R²³, or R²⁴ and R²⁵ are independently selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂, and O, all of which may be substituted with 1-3 of R¹⁰, or R²⁴ and R²⁵ are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R¹⁰, or R²⁴ and R²⁵ combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂, and O, or a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), all of which may be substituted with 1-3 of R¹⁰; R²⁶ is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR²²)—R²³, and A-R²³, or R²⁶ is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂, and O, all of which may be substituted with 1-3 of R¹⁰, or R²⁶ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R¹⁰; R27 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A-R²³, or R²⁷ is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂, and O, all of which may be substituted with 1-3 of R¹⁰, or R ²⁷ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R¹⁰; R²⁸ is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R²³, C(═O)R²⁴, C(═O)OR²⁶, C(═O)NR²⁵R³⁰, S(═O)R²⁶, A-C(═O)R²⁴, A-C(═O)OR²⁴, and A-C(═O)NR²⁴R²⁵, or R²⁸ is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂, and O, all of which may be substituted with 1-3 of R¹⁰, or R²⁸ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R¹⁰; R³⁰ is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR²²)—R²³, and A-R²³, or R³⁰ is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂, and O, all of which may be substituted with 1-3 of R¹⁰, or R³⁰ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R¹⁰, or R²⁵ and R³⁰ combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(═O)₀₋₂, and O, or a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, all of which may be substituted with 1-3 of R¹⁰; R²⁹ is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A-R²³, A-C(═O)R²⁴, A-C(═O)OR²⁴, A-C(═O)NR²⁴R²⁵, A-NR²⁷R²⁸, or R²⁹ is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(═O)₀₋₂, and O, all of which may be substituted with 1-3 of R¹⁰, or R²⁹ is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(═O)₀₋₂, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(═O)₀₋₂ and O, and/or wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R¹⁰; and pharmaceutically acceptable salts thereof.
 2. The method of claim 1, wherein said compound is administered as a single daily dose.
 3. The method of claim 1, wherein said compound is administered as a tablet.
 4. The method of claim 3, wherein said compound is administered as a sustained released form. 